Molecular recognition mechanisms of thrombin.
Thrombin is the final protease generated in the blood coagulation cascade, and is the only factor capable of cleaving fibrinogen to create a fibrin clot. Unlike every other coagulation protease, thrombin is composed solely of its serine protease domain, so that once formed it can diffuse freely to encounter a large number of potential substrates. Thus thrombin serves many functions in hemostasis through the specific cleavage of at least a dozen substrates. The solution of the crystal structure of thrombin some 15 years ago revealed a deep active site cleft and two adjacent basic exosites, and it was clear that thrombin must utilize these unique features in recognizing its substrates. Just how this occurs is still being investigated, but recent data from thrombin mutant libraries and crystal structures combine to paint the clearest picture to date of the molecular determinants of substrate recognition by thrombin. In almost all cases, both thrombin exosites are involved, either through direct interaction with the substrate protein or through indirect interaction with a third cofactor molecule. The purpose of this article is to summarize recent biochemical and structural data in order to provide insight into the thrombin molecular recognition events at the heart of hemostasis.
Huntington
J A
JA
Department of Haematology, Cambridge Institute for Medical Research, Division of Structural Medicine, Thrombosis Research Unit, University of Cambridge, Cambridge, UK. jah52@cam.ac.uk
D000818:Animals; D005165:Factor V / Q000737:chemistry; D005172:Factor XI / Q000737:chemistry; D005176:Factor XIII / Q000737:chemistry; D005340:Fibrinogen / Q000737:chemistry; D006487:Hemostasis; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry; D008954:Models, Biological; D008958:Models, Molecular; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D044462:Receptors, Proteinase-Activated / Q000737:chemistry; D013379:Substrate Specificity; D013917:Thrombin / Q000737:chemistry* / Q000502:physiology*
D046911:Macromolecular Substances; D019038:Platelet Glycoprotein GPIb-IX Complex; D044462:Receptors, Proteinase-Activated; D005165:Factor V; D005340:Fibrinogen; D005172:Factor XI; D005176:Factor XIII; D013917:Thrombin