5DUS,2ACF,2FAV,2VRI,3EJF,3EJG,3EKE,3ETI,3EW5,3EWO,3EWQ,3GPG,3GPO,3GQE,4GUA,5HIH,5MQX,6MEA,6W02,7JME,6WOJ


Conserved Protein Domain Family
Macro_X_Nsp3-like

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cd21557: Macro_X_Nsp3-like 
Click on image for an interactive view with Cn3D
X-domain (or Mac1 domain) of viral non-structural protein 3 and related macrodomains
The X-domain, also called Mac1, is the macrodomain found in riboviral non-structural protein 3 (Nsp3), including the Nsp3 of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) as well as SARS-CoV-2, and other coronaviruses (alpha-, beta-, gamma-, and deltacoronavirus), among others. The SARS-CoV-2 Nsp3 Mac1 is highly conserved among all CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. It appears to counter host-mediated antiviral ADP-ribosylation, a post-translational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Assays show that the de-MARylating activity leads to a rapid loss of substrate, and that Mac1 could not hydrolyze poly-ADP-ribose; thus, Mac1 is a MAR-hydrolase (mono-ADP ribosylhydrolase). Mac1 was originally named ADP-ribose-1"-phosphatase (ADRP) based on data demonstrating that it could remove the phosphate group from ADP-ribose-1"-phosphate; however, activity was modest and was unclear why this would impact a virus infection. This family also includes the X-domain of Avian infectious bronchitis virus (IBV) strain Beaudette coronavirus that does not bind ADP-ribose; the triple glycine sequence found in the X-domains of SARS-CoV and human coronavirus 229E (HCoV229E), which are involved in ADP-ribose binding, is not conserved in the IBV X-domain. SARS-CoVs have two other macrodomains referred to as the SUD-N (N-terminal subdomain, or Mac2) and SUD-M (middle SUD subdomain, or Mac3) of the SARS-unique domain (SUD), which also do not bind ADP-ribose; these bind G-quadruplexes (unusual nucleic-acid structures formed by consecutive guanosine nucleotides). SARS-CoV SUD-N and SUD-M are not included in this group.
Statistics
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PSSM-Id: 438957
Aligned: 118 rows
Threshold Bit Score: 100.322
Created: 25-Mar-2020
Updated: 25-Oct-2021
Structure
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Program:
Drawing:
Aligned Rows:
 
ADP-ribose
Conserved site includes 18 residues -Click on image for an interactive view with Cn3D
Feature 1:ADP-ribose binding site [chemical binding site]
Evidence:
  • Comment:not all macrodomains belonging to this family bind ADP-ribose, for example the X-domain of Avian infectious bronchitis virus (IBV) strain Beaudette coronavirus
  • Structure:6W02: SARS-CoV-2 Nsp3 macrodomain binds ADP-ribose; contacts at 4A
  • Structure:6MEA: Tylonycteris bat coronavirus HKU4 macrodomain binds adenosine-5-diphosphoribose, contacts at 4A
  • Structure:5DUS: Middle East respiratory syndrome-related coronavirus (MERS-CoV) macrodomain binds adenosine-5-diphosphoribose, contacts at 4A
  • Structure:6WOJ: SARS-CoV-2 Nsp3 macrodomain binds ADP-ribose; contacts at 4A

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
Feature 1               ###   #######                                                             
5DUS_A         34 ESVLVNAANTHLKHGGGIAGAINAaskgavqkesdeyilakgplqvGDSVLLQghslakNILHVVGPDArakq----dvs 109  Middle East r...
6W02_A         32 PTVVVNAANVYLKHGGGVAGALNKatnnamqvesddyiatngplkvGGSCVLSghnlakHCLHVVGPNVnkge----diq 107  Severe acute ...
AFU92103     1312 HDFVVNAANENLSHGGGVAAAINNltkgllqtlsdhyvkkngkikvGQGVMLHcg--keNVLNVVGPRKgkh-----spq 1384 Rousettus bat...
AIA62199     1450 FDFIVNAANENLKHAGGVAAAIDKltgnelqslsnkyvkangkvkvGSGVMIRck--kySVLNVVGPRKgkh-----ape 1522 BtMf-AlphaCoV...
YP_009201729 1150 HDFVVNAANERLQHGGGVAKAINDytnnelqhlssahvkkhgkvsvGSGVMLQcs--gvKVLNVVGPRHgag-----eva 1222 BtNv-AlphaCoV...
ANA96047      913 FDFIVNAANENLSHGGGIAKAIDDvsngtlqqvsniwiksngklkvGSGVMLHvd--glSVYNVVGPRKgkh-----ase 985  Bat coronavirus
AZF86117     1166 HDFIVNAANENLQHGGGVAKAISVctkgelqklsdayvkqngklkvGAGVMLDca--plKVFNVVGPRKgkh-----drd 1238 Alphacoronavi...
AZF86129     1201 HDFVVNAANSELKHGGGVAAAINVftkgllqdlsnkhiaihgpvkvGDGVMIVcg--diNVFNVVGPRKgkf-----ase 1273 Alphacoronavi...
QBP43288     1256 HDFIVNAANENLSHGGGVAAAIDNltkgqlqklstahvkangkvkvGGGVMLKce--khSVLNVVGPRNgkh-----apt 1328 Bat coronavirus
QCX35159     1150 HDFVVNAANENLQHGGGVAKAIDVytngtlqresvkyvkangqvrkGHGVMLDcd--giNVFNVVGPRKtkkcsissckd 1227 Tylonycteris ...
Feature 1                           ## #####                        # 
5DUS_A        110 LLSKCYKAMna-ypLVVTPLVSAGIFgvKPAVSFDYLIREAKt---RVLVVV 157  Middle East respiratory syndrome-related ...
6W02_A        108 LLKSAYENFnq-heVLLAPLLSAGIFgaDPIHSLRVCVDTVRt---NVYLAV 155  Severe acute respiratory syndrome coronav...
AFU92103     1385 LLEKAYKFVlkqkgTPLTPLLSVGIFkvPILESVTALKNVVGdrhvKCFCYS 1436 Rousettus bat coronavirus HKU10
AIA62199     1523 LLEKCYRTIlkeqgVPLTPLISVGIFgiPLATSFNALLNTSSgrtvRCFCYT 1574 BtMf-AlphaCoV/AH2011
YP_009201729 1223 LLENAYNCIfdqdgVPLTPLIGVGIFkvPITTSLKALLDVVGdrqcRCFCYS 1274 BtNv-AlphaCoV/SC2013
ANA96047      986 LLTKAYNSIfsnsgVPLTPLISIGIFkvPIHDSLSALLATVGd--rDCLCFC 1035 Bat coronavirus
AZF86117     1239 LLTKAYKSVfanagVPLTPLLSVGIFnvPLTTSLEVFLKEVDdrvcKCFCYS 1290 Alphacoronavirus Bat-CoV/P.kuhlii/Italy/2...
AZF86129     1274 LLVKAYKSVlsnqgTPLMPMISVGIFgiDMVTSMDAFFSVVGdrhcKCFCYT 1325 Alphacoronavirus Bat-CoV/P.kuhlii/Italy/2...
QBP43288     1329 LLEKAYGTVfnesgIPLTPLLSVGIFkvPLETSLDALFNVVGdkvvKCFCYT 1380 Bat coronavirus
QCX35159     1228 ALLQAYTAVynnngVPLTPLLSVGIFgvPIDISLSVFLDVTGervsNCFCYT 1279 Tylonycteris bat coronavirus HKU33

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