Anticoagulant proteins from snake venoms: structure, function and mechanism

Abstract

Over the last several decades, research on snake venom toxins has provided not only new tools to decipher molecular details of various physiological processes, but also inspiration to design and develop a number of therapeutic agents. Blood circulation, particularly thrombosis and haemostasis, is one of the major targets of several snake venom proteins. Among them, anticoagulant proteins have contributed to our understanding of molecular mechanisms of blood coagulation and have provided potential new leads for the development of drugs to treat or to prevent unwanted clot formation. Some of these anticoagulants exhibit various enzymatic activities whereas others do not. They interfere in normal blood coagulation by different mechanisms. Although significant progress has been made in understanding the structure-function relationships and the mechanisms of some of these anticoagulants, there are still a number of questions to be answered as more new anticoagulants are being discovered. Such studies contribute to our fight against unwanted clot formation, which leads to death and debilitation in cardiac arrest and stroke in patients with cardiovascular and cerebrovascular diseases, arteriosclerosis and hypertension. This review describes the details of the structure, mechanism and structure-function relationships of anticoagulant proteins from snake venoms.

Figure 1. Structure–function relationships of anticoagulant proteins

(A) The predicted anticoagulant region of anticoagulant PLA₂ enzymes [26]. The ribbon model of N. naja PLA₂ was generated from the PDB file (#1POA) [171]. The predicted anticoagulant region (highlighted in red) is fully exposed on the surface and easily accessible for interaction. Tryptophan residues are shown in yellow. (B) The binding site of FIX/FX-binding protein. The ribbon model was generated from the PDB file (#1IXX) [99]. The concave central region formed through domain swapping between the two subunits is the binding site for the Gla domain [108,109], and is indicated by the white broken line).