Procoagulant Proteins and Diagnostic Agents Haemostasis 2001;31:247–256 Molecular Basis for the Partition of the Essential Functions of Thrombin among Snake Venom Serine Proteinases The Case of Thrombin-Like Enzymes R.C. Maroun Unité des Venins, Institut Pasteur, Paris, France R.C. Maroun Unité des Venins, Institut Pasteur 25, rue du Docteur-Roux, F–75724 Paris Cedex 15 (France) Tel. +33 1 40 61 34 97, Fax +33 1 40 61 30 57 E-Mail rmaroun@pasteur.fr ABC Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com © 2002 S. Karger AG, Basel 0301–0147/01/0316–0247$17.50/0 Accessible online at: www.karger.com/journals/hae Key Words Thrombin W Snake venoms W Thrombin-like serine proteinases W Molecular modeling W Molecular recognition Abstract Thrombin is a mammalian serine proteinase that plays a prominent role in the mainte- nance and regulation of hemostasis through its interaction with various substrates and/or ligands. The venoms of several snakes con- tain glycosylated serine proteinases that have been recognized to possess one or more of the essential activities of thrombin on fibrinogen (Fg) and/or platelets. These proteinases share about 60% sequence iden- tity. One class of snake venom serine protein- ases are those known as thrombin-like (TLE), named after their ability to directly clot Fg in order to preferentially produce fibrinopep- tide A, fibrinopeptide B or both. To under- stand the molecular basis of this phenome- non, the corresponding amino acid se- quences and molecular structures need to be analyzed. Given the absence of experimen- tally determined tertiary structures of snake venom, TLEs, three-dimensional molecular models should prove useful in this context. Towards this goal, we obtained models of snake venom TLEs that used TSV-PA as tem- plate, TSV-PA being the only snake venom serine proteinase whose crystal structure is known to date. Along with a comparative sequence analysis the models contribute to the identification and description of throm- bin-homologous or alternative binding sites, helping thus to understand differences in specificity. Copyright © 2002 S. Karger AG, Basel Introduction Serine proteinases of a given fold share an identical catalytic mechanism, but markedly differ in substrate specificity [1–3], a property that is the outcome of evolutionary diver-