2afq
From Proteopedia
|
1.9 angstrom crytal structure of wild-type human thrombin in the sodium free state
Contents |
Overview
Regulation of thrombin activity is critical for haemostasis and the, prevention of thrombosis. Thrombin has several procoagulant substrates, including fibrinogen and platelet receptors, and essential cofactors for, stimulating its own formation. However, thrombin is also capable of, serving an anticoagulant function by activating protein C. The specificity, of thrombin is primarily regulated by binding to the cofactor TM, (thrombomodulin), but co-ordination of Na+ can also affect thrombin, activity. The Na+-free form is often referred to as 'slow' because of, reduced rates of cleavage of procoagulant substrates, but the slow form is, still capable of rapid activation of protein C in the presence of TM. The, molecular basis of the slow proteolytic activity of thrombin has remained, elusive, in spite of two decades of solution studies and many published, crystallographic structures. In the present paper, we report the first, structure of wild-type unliganded human thrombin grown in the absence of, co-ordinating Na+. The Na+-binding site is observed in a highly ordered, position 6 A (1 A=0.1 nm) removed from that seen in the Na+-bound state., The movement of the Na+ loop results in non-catalytic hydrogen-bonding in, the active site and blocking of the S1 and S2 substrate-binding pockets., Similar, if more dramatic, changes were observed in a previous structure, of the constitutively slow thrombin variant E217K. The slow behaviour of, thrombin in solutions devoid of Na+ can now be understood in terms of an, equilibrium between an inert species, represented by the crystal structure, described in the present paper, and an active form, where the addition of, Na+ populates the active state.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
2AFQ is a Protein complex structure of sequences from Homo sapiens with GOL as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
Reference
Crystal structure of wild-type human thrombin in the Na+-free state., Johnson DJ, Adams TE, Li W, Huntington JA, Biochem J. 2005 Nov 15;392(Pt 1):21-8. PMID:16201969
Page seeded by OCA on Mon Nov 12 20:50:27 2007
