extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRRL 66
Cdd:cd19017  116 MKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFIIRRL 181

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                         90
                 ....*....|
gi 375151585 148 TVFVLNVHHR 157
Cdd:cd19064   81 TVIVLNVHHR 90

extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 4 (alpha4), encoded by the CHRNA4 gene. Alpha4 forms a functional nAChR by interacting with either nAChR beta2 or beta4 subunits. Alpha4beta2, the major heteropentameric nAChR in the brain, exists in two isoforms, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, with the latter believed to constitute the majority of alpha4beta2 nAChR in the cortex. Both isoforms contain two canonical alpha4:beta2 ACh-binding sites with either low or high ACh sensitivity. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene (CHRNA4) cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene may provide protection against nicotine addiction.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRRL 66
Cdd:cd19017  116 MKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFIIRRL 181

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  210 PEPEGEPPATSGTQSLHPPS-------PSFCVPLDVPAEPG-PSCKSPSDQLPPQQPLEAEKAS--PHPSPGPCRPPHGT 279
Cdd:PHA03247 2754 PARPARPPTTAGPPAPAPPAapaagppRRLTRPAVASLSESrESLPSPWDPADPPAAVLAPAAAlpPAASPAGPLPPPTS 2833

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  280 QAPGLAKARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDDAA---PEADGQAAGALaSRNTHSAELPPPDQPSPCKCT 356
Cdd:PHA03247 2834 AQPTAPPPPPGPPPPSLPLGGSVAPGGDVRRRPPSRSPAAKPAAparPPVRRLARPAV-SRSTESFALPPDQPERPPQPQ 2912

                         170       180       190
                  ....*....|....*....|....*....|.
gi 375151585  357 CKKEPSSVSPSATVKTRSTKAPPPHLPLSPA 387
Cdd:PHA03247 2913 APPPPQPQPQPPPPPQPQPPPPPPPRPQPPL 2943

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                         90
                 ....*....|
gi 375151585 148 TVFVLNVHHR 157
Cdd:cd19064   81 TVIVLNVHHR 90

extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 4 (alpha4), encoded by the CHRNA4 gene. Alpha4 forms a functional nAChR by interacting with either nAChR beta2 or beta4 subunits. Alpha4beta2, the major heteropentameric nAChR in the brain, exists in two isoforms, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, with the latter believed to constitute the majority of alpha4beta2 nAChR in the cortex. Both isoforms contain two canonical alpha4:beta2 ACh-binding sites with either low or high ACh sensitivity. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene (CHRNA4) cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene may provide protection against nicotine addiction.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRRL 66
Cdd:cd19017  116 MKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFIIRRL 181

transmembrane domain of Cys-loop neurotransmitter-gated ion channels, includes 5HT3, nAChR, and ZAC; This superfamily contains the transmembrane (TM) domain of cationic Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), and zinc-activated ligand-gated ion channel (ZAC) receptor. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The ligand-gated ion channels (LGICs) in this family are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+ and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling require is as yet unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19051    1 LFYVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTSDSVPLIGIYLLATMVLSALSTVL 80

                         90       100
                 ....*....|....*....|....*.
gi 375151585 148 TVFVLNVHHRSPRthtMPTWVRRVFL 173
Cdd:cd19051   81 TVIVLNLHHVLDR---LFFWLFLLVT 103

extracellular domain of nicotinic acetylcholine receptor; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits, and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd18997  116 LKFGSWTYDGSELDLQLKSDTVDLSDYIENGEWDLLGAPAKRNVVKYSCCPEPYPDVTFTIHIRR 180

extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYEccAEIYPDITYAFVIRRL 66
Cdd:cd03558  116 MKLESWTYDTTDIELVWDSERPDQADFLELPEWDIVEKRGRYCTVVYN--TGIYSDITYRFRLKRQ 179

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCaeIYPDITYAFVIRRLPL 68
Cdd:cd19018  142 MKFGSWTYDGSQVDIILEDYDVDKRDFFDNGEWEIVSATGSKGNRTDGCC--WYPFITYSFIIRRLPL 207

extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (CHRNB3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (beta3), encoded by the CHRNB3 gene. CHRNB3 polymorphisms have been reported to potentially affect nicotine-induced upregulation of nicotinic and to be associated with disorders such as schizophrenia, autism, and cancer. Beta3 subunit is depleted in the striatum of Parkinson's disease patients. Rare variants in CHRNB3 are also implicated in risk for alcohol and cocaine dependence and independently associated with bipolar disorder. Human alpha6beta2beta3* (* indicating possible additional assembly partners) nAChRs on dopaminergic neurons are important targets for drugs to treat nicotine addiction and Parkinson's disease; (alpha6beta2)(alpha4beta2)beta3 nAChR is essential for addiction to nicotine and a target for drug development for smoking cessation.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAeiYPDITYAFVIRRL 66
Cdd:cd19026  116 MKFGSWTYDGNMVDLILIDENVDRKDFFDNGEWEILNAKGMKGNRKDGLYS--YPFITYSFVLRRL 179

extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 10 (alpha10), encoded by the CHRNA10 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Unlike alpha9 nAChR subunits, alpha10 subunits do not generate functional channels when expressed heterologously, suggesting that alpha10 might serve as a structural subunit, much like a beta subunit of heteromeric receptors, providing only complementary components to the agonist binding site. Mammalian alpha10 subunits can form functional heteromeric alpha9alpha10 receptors, an atypical heteromeric receptor since it is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd19023  116 LTFGSWTYNGNQIDILNLLDTGDLTDFVENVEWEVLGMPAKRNVITYGCCSEPYPDVTYTLLLKR 180

acetylcholine binding protein (AChBP); This family contains acetylcholine binding protein (AChBP) which is a soluble extracellular domain homolog secreted by protostomia, and has been widely recognized as a surrogate for the ligand binding domain of nicotinic acetylcholine receptors (nAChRs). AChBP forms a pentameric structure where the interfaces between the subunits provide an acetylcholine (ACh) binding pocket homologous to the binding pocket of nAChRs. Thus far, AChBPs have been characterized only in aquatic mollusks, which have shown low sensitivity to neonicotinoids, the insecticides targeting insect nAChRs. Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) which has been found in glial cells as a water-soluble protein modulating synaptic ACh concentration has its the binding pocket show better resemblance as it contains all the five aromatic residues fully conserved in nAChR. Five AChBP subunits have been characterized in Pardosa pseudoannulata, a predator enemy against rice insect pests, and share higher sequence similarities with nAChR subunits of both insects and mammals compared with mollusk AChBP subunits.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 375151585   2 KFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd18995  116 KIGSWTYSGREIDLNTGTDVDLDSYYNQSSKWELLSATQKREVKTYSCCPEPYPDIEFVFTFKK 179

extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (CHRNA1); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (alpha1), encoded by the CHRNA1 gene. These muscle type nicotinic subunits form heteropentamers with other nAChR subunits, most broadly expressed as combination of two alpha1, beta1, delta, and epsilon subunits in mature muscles, and of two alpha1, beta1, delta, and gamma in embryonic cells. The alpha1 subunit in human nAChR is the primary target of Myasthenia gravis antibodies that disrupt communication between the nervous system and the muscle, causing chronic muscle weakness.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEI-YPDITYAFVIRRLP 67
Cdd:cd19014  143 MKLGTWTYDGTLVVINPESDRPDLSNFMESGEWVMKDYRGWKHWVYYTCCPDTpYLDITYHFLLQRLP 210

transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains transmembrane (TM) domain of the serotonin 5-HT3 receptors. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The 5-HT3 channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGTPLIGVYFVVCLALMVLSLLE 80

                 ....*....
gi 375151585 148 TVFVLNVHH 156
Cdd:cd19063   81 TILIVKLLH 89

extracellular domain of neuronal acetylcholine receptor subunit alpha-7-like; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDqlDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd19021  116 LKFGSWTHSGWLIDLQMLEADIS--NYISNGEWDLVGVPGKRNELYYECCKEPYPDVTYTITMRR 178

extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 375151585   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGtyntRKYECCAE-IYPDITYAFVIRR 65
Cdd:cd19027  116 LKFRSWTYDHTEIDMVLKTPTASMDDFTPSGEWDIVALPG----RRTVNPLDpTYVDVTYDFIIKR 177

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  210 PEPEGEPPATSGTQSLHPPS-------PSFCVPLDVPAEPG-PSCKSPSDQLPPQQPLEAEKAS--PHPSPGPCRPPHGT 279
Cdd:PHA03247 2754 PARPARPPTTAGPPAPAPPAapaagppRRLTRPAVASLSESrESLPSPWDPADPPAAVLAPAAAlpPAASPAGPLPPPTS 2833

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  280 QAPGLAKARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDDAA---PEADGQAAGALaSRNTHSAELPPPDQPSPCKCT 356
Cdd:PHA03247 2834 AQPTAPPPPPGPPPPSLPLGGSVAPGGDVRRRPPSRSPAAKPAAparPPVRRLARPAV-SRSTESFALPPDQPERPPQPQ 2912

                         170       180       190
                  ....*....|....*....|....*....|.
gi 375151585  357 CKKEPSSVSPSATVKTRSTKAPPPHLPLSPA 387
Cdd:PHA03247 2913 APPPPQPQPQPPPPPQPQPPPPPPPRPQPPL 2943

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  200 HKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGPSckSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGT 279
Cdd:PHA03307  142 GSPGPPPAASPPAAGASPAAVASDAASSRQAALPLSSPEETARAPS--SPPAEPPPSTPPAAASPRPPRRSSPISASASS 219

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  280 QAPGLAK-----ARSLSVQHMSSPGEAVEGGVRCR------SRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPD 348
Cdd:PHA03307  220 PAPAPGRsaaddAGASSSDSSSSESSGCGWGPENEcplprpAPITLPTRIWEASGWNGPSSRPGPASSSSSPRERSPSPS 299

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|.
gi 375151585  349 QPSPCKCTC------KKEPSSVSPSATVKTRSTKAPP--PHLPLSPALTRA 391
Cdd:PHA03307  300 PSSPGSGPApsspraSSSSSSSRESSSSSTSSSSESSrgAAVSPGPSPSRS 350

DNA polymerase III subunits gamma and tau; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585 216 PPATSGTQSLHPP---SPSFCVPLDVPAEPGPSCKSPSDQLPPQQPLEAEKASPHP-----SPGPCRPPHGTQAPGLAKA 287
Cdd:PRK14959 399 TPGTQGPQGTAPAagmTPSSAAPATPAPSAAPSPRVPWDDAPPAPPRSGIPPRPAPrmpeaSPVPGAPDSVASASDAPPT 478

                         90       100       110
                 ....*....|....*....|....*....|...
gi 375151585 288 RSLSvqhmSSPGEAVEGGVRCRSRSIQYCVPRD 320
Cdd:PRK14959 479 LGDP----SDTAEHTPSGPRTWDGFLEFCQGRN 507

104 kDa microneme/rhoptry antigen; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585 181 LMKRPSVVKDncrrliesmhkmASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPG--PSCKSPSDQLPPQQP 258
Cdd:PTZ00449 575 LSKKPEFPKD------------PKHPKDPEEPKKPKRPRSAQRPTRPKSPKLPELLDIPKSPKrpESPKSPKRPPPPQRP 642

                         90       100
                 ....*....|....*....|....
gi 375151585 259 LEAEKASPHPSPGPCRPPHGTQAP 282
Cdd:PTZ00449 643 SSPERPEGPKIIKSPKPPKSPKPP 666

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  204 SAPRFWPEPEGEPPATSGTQSLHPPSPSfcvPLDVPAEPGPSCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPG 283
Cdd:PHA03307  130 PAPDLSEMLRPVGSPGPPPAASPPAAGA---SPAAVASDAASSRQAALPLSSPEETARAPSSPPAEPPPSTPPAAASPRP 206

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  284 LAKARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDDAAPEADGQAAGALaSRNTHSAELPPPDQPSPCKCTcKKEPSS 363
Cdd:PHA03307  207 PRRSSPISASASSPAPAPGRSAADDAGASSSDSSSSESSGCGWGPENECPL-PRPAPITLPTRIWEASGWNGP-SSRPGP 284

                         170       180       190
                  ....*....|....*....|....*....|..
gi 375151585  364 VSPSATVKTRSTKAPP--PHLPLSPALTRAVE 393
Cdd:PHA03307  285 ASSSSSPRERSPSPSPssPGSGPAPSSPRASS 316

104 kDa microneme/rhoptry antigen; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585 193 RRLIE-SMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGPSCKSPSDQLPPQQPLEAEKASphpSPG 271
Cdd:PTZ00449 486 KKLIKkSKKKLAPIEEEDSDKHDEPPEGPEASGLPPKAPGDKEGEEGEHEDSKESDEPKEGGKPGETKEGEVGK---KPG 562

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585 272 PCRPPHGTQAPGLAKARSL--SVQHMSSPGEaveggvrcrsrsiqycvPRDDAAPEADGQAAGALASRNTHSAELPPPDQ 349
Cdd:PTZ00449 563 PAKEHKPSKIPTLSKKPEFpkDPKHPKDPEE-----------------PKKPKRPRSAQRPTRPKSPKLPELLDIPKSPK 625

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 375151585 350 PSPCKCTCKKEPSSVSPSATVKTRSTKAP-PPHLPLSP 386
Cdd:PTZ00449 626 RPESPKSPKRPPPPQRPSSPERPEGPKIIkSPKPPKSP 663

transmembrane domain of prokaryotic pentameric ligand-gated ion channels (pLGIC); This family contains transmembrane (TM) domain of bacterial pentameric ligand-gated ion channels (pLGICs) including ones from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. Studies show that GLIC activation is inhibited by most general anaesthetics at clinical concentrations, including xenon which has been used in clinical practice as a potent gaseous anesthetic for decades. Xenon binding sites have been identified in three distinct regions of the TMD: in a large intra-subunit cavity, in the pore, and at the interface between adjacent subunits. Propofol, the drug used for induction and maintenance of general anesthesia, and desflurane, a negative allosteric modulator of GLIC bind at the entrance in the intra-subunit cavity. Alzheimer's drug memantine, which blocks ion conduction at vertebrate pLGICs by plugging the channel pore, has been shown to have similar potency in ELIC.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  69 FYTINLIIPCLLISCLTVLVFYL-PSECGEKITLCISVLLSLTVFLLLITEIIPSTSLvIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19050    1 YYIWKVILPLLLIVAMSWSVFWIdPESFGPQIGISVTSMLTLIAFNFLISNSLPRLPY-LTFMDAFILASYLLVFLALIE 79

                         90       100
                 ....*....|....*....|....*..
gi 375151585 148 TVFV--LNVHHRSPRTHTMPTWVRRVF 172
Cdd:cd19050   80 VIVThyLARNGKEALALRIDRISRWAF 106

DNA polymerase III subunit gamma/tau;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585 203 ASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPlDVPAEPGPSCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAP 282
Cdd:PRK12323 378 AAAPVAQPAPAAAAPAAAAPAPAAPPAAPAAAP-AAAAAARAVAAAPARRSPAPEALAAARQASARGPGGAPAPAPAPAA 456

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585 283 GLAKARSLSVQHMSSPGEAVEGGVRCRSRSIQyCVPRDDAAPEADgQAAGALASrnthsaelPPPDQPSPCKCTCKKEPS 362
Cdd:PRK12323 457 APAAAARPAAAGPRPVAAAAAAAPARAAPAAA-PAPADDDPPPWE-ELPPEFAS--------PAPAQPDAAPAGWVAESI 526

                        170       180       190
                 ....*....|....*....|....*....|....
gi 375151585 363 S-VSPSATVKTRSTKAPPPHLPLSPALTRAVEGV 395
Cdd:PRK12323 527 PdPATADPDDAFETLAPAPAAAPAPRAAAATEPV 560

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  204 SAPRFWPEPEGEPPATSGTqslhPPSPSFCVPLDVPAEP--------------------GPSCKSPSDQLPPQQPLEA-E 262
Cdd:PHA03247 2490 FAAGAAPDPGGGGPPDPDA----PPAPSRLAPAILPDEPvgepvhprmltwirgleelaSDDAGDPPPPLPPAAPPAApD 2565

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 375151585  263 KASPHPSPGPcRPPHgtQAPGLAKARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDDAAPE--ADGQAAGALASRNTH 340
Cdd:PHA03247 2566 RSVPPPRPAP-RPSE--PAVTSRARRPDAPPQSARPRAPVDDRGDPRGPAPPSPLPPDTHAPDppPPSPSPAANEPDPHP 2642

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 375151585  341 SAELPPPDQPSPckctcKKEPSSVSPS--ATVKTRSTKAP-PPHLPLSPALTRAVEGVQYIAD 400
Cdd:PHA03247 2643 PPTVPPPERPRD-----DPAPGRVSRPrrARRLGRAAQASsPPQRPRRRAARPTVGSLTSLAD 2700