1sr5
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ANTITHROMBIN-ANHYDROTHROMBIN-HEPARIN TERNARY COMPLEX STRUCTURE
OverviewOverview
Antithrombin, the principal physiological inhibitor of the blood coagulation proteinase thrombin, requires heparin as a cofactor. We report the crystal structure of the rate-determining encounter complex formed between antithrombin, anhydrothrombin and an optimal synthetic 16-mer oligosaccharide. The antithrombin reactive center loop projects from the serpin body and adopts a canonical conformation that makes extensive backbone and side chain contacts from P5 to P6' with thrombin's restrictive specificity pockets, including residues in the 60-loop. These contacts rationalize many earlier mutagenesis studies on thrombin specificity. The 16-mer oligosaccharide is just long enough to form the predicted bridge between the high-affinity pentasaccharide-binding site on antithrombin and the highly basic exosite 2 on thrombin, validating the design strategy for this synthetic heparin. The protein-protein and protein-oligosaccharide interactions together explain the basis for heparin activation of antithrombin as a thrombin inhibitor.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1SR5 is a Protein complex structure of sequences from Homo sapiens with , and as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity., Dementiev A, Petitou M, Herbert JM, Gettins PG, Nat Struct Mol Biol. 2004 Sep;11(9):863-7. Epub 2004 Aug 15. PMID:15311268
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