PAK: an essential motif for forming beta-turn structures and exhibiting the thrombolytic effect of P6A and its analogs

Biochem Cell Biol. 2007 Dec;85(6):730-40. doi: 10.1139/o07-143.

Abstract

Ala-Arg-Pro-Ala-Lys (ARPAK; also known as P6A) and 19 of its analogs were synthesized, and their thrombolytic activities were assessed in vitro and in vivo. The solution structures of 12 of the P6A analogs were determined using nuclear magnetic resonance (NMR) spectroscopy. The thrombolytic activity and conformational structure relationship was analyzed. We found that the Pro-Ala-Lys (PAK) sequence was essential for thrombolytic activity and was also responsible for the beta-turn structure found in the P6A analogs studied. The well defined beta turn may act as a binding head with the protruding lysine side-chain (positively charged) found at the target site for target recognition. Additionally, the N-terminal residue may be critical for thrombolytic activity, which for PAK-containing peptides, is likely achieved via a plasminogen-dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Blood Coagulation / drug effects
  • Fibrin Fibrinogen Degradation Products / chemical synthesis
  • Fibrin Fibrinogen Degradation Products / chemistry*
  • Fibrin Fibrinogen Degradation Products / metabolism*
  • Fibrinolysis / drug effects
  • Fibrinolysis / physiology*
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / pharmacology
  • Protein Structure, Secondary
  • Rabbits
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Temperature
  • Time Factors

Substances

  • Fibrin Fibrinogen Degradation Products
  • Peptides
  • fibrinogen peptide 6A