Structural features of a snake venom thrombin-like enzyme: thrombin and trypsin on a single catalytic platform?

Biochim Biophys Acta. 2001 Jun 11;1547(2):183-95. doi: 10.1016/s0167-4838(01)00177-7.

Abstract

The Lachesis muta thrombin-like enzyme (LM-TL) is a single chain serine protease that shares 38% sequence identity with the serine protease domain of thrombin and also displays similar fibrinogen-clotting activity. In addition, the 228 amino acid residue LM-TL is 52% identical to trypsin, and cleaves chromogenic substrates with similar specificity. Herein we report a three-dimensional (3D) model validated experimentally for LM-TL based on these two homologous proteins of known 3D structure. Spatial modeling of LM-TL reveals a serine protease with a chymotrypsin fold presenting a hydrophobic pocket on its surface, involved in substrate recognition, and an important 90's loop, involved in restricting the LM-TL catalytic site cleft. Docking analysis showed that LM-TL would not form a stable complex with basic pancreatic trypsin inhibitor and wild-type ecotin since its 90's loop would restrict the access to the catalytic site. LM-TL formed acceptable interactions with fibrinopeptide A and a variant of ecotin; ecotin-TSRR/R in which both the primary and secondary binding sites are mutated Val81Thr, Thr83Ser, Met84Arg, Met85Arg and Asp70Arg. Furthermore, analysis of the primary structures of LM-TL and of the seven snake venom thrombin-like enzymes (SVTLEs) family reveals a subgroup formed by LM-TL, crotalase, and bilineobin, both closely related to thrombin. Therefore, LM-TL provides an initial point to compare SVTLEs with their counterparts, e.g. the mammalian serine proteases, and a basis for the localization of important residues within the little known SVTLEs family.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Binding Sites
  • Crotalid Venoms / chemistry*
  • Escherichia coli Proteins*
  • Fibrinogen / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Periplasmic Proteins*
  • Protein Structure, Secondary
  • Sequence Alignment
  • Serine Endopeptidases / chemistry
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / genetics
  • Thrombin / antagonists & inhibitors
  • Thrombin / chemistry*
  • Trypsin / chemistry*
  • Trypsin Inhibitors / chemistry

Substances

  • Bacterial Proteins
  • Crotalid Venoms
  • Eco protein, E coli
  • Escherichia coli Proteins
  • Lachesis venom
  • Periplasmic Proteins
  • Serine Proteinase Inhibitors
  • Trypsin Inhibitors
  • Fibrinogen
  • Serine Endopeptidases
  • Trypsin
  • Thrombin