1SR5

ANTITHROMBIN-ANHYDROTHROMBIN-HEPARIN TERNARY COMPLEX STRUCTURE

Summary for 1SR5

• Entry DOI: 10.2210/pdb1sr5/pdb
• Related PRD ID: PRD_900079
• Descriptor: Antithrombin-III, Prothrombin, 4-deoxy-2,3,6-tri-O-methyl-alpha-D-xylo-hexopyranose-(1-4)-2,3,6-tri-O-methyl-beta-D-glucopyranose-(1-4)-2,3-di-O-methyl-6-O-sulfo-alpha-D-glucopyranose-(1-4)-(2R,3R,4S,5S,6S)-6-(dihydroxymethyl)-3,4-dimethoxytetrahydro-2H-pyran-2,5-diol-(1-4)-2,3,6-tri-O-sulfo-alpha-D-glucopyranose-(1-4)-(2R,3R,4S,5S,6R)-6-(dihydroxymethyl)-3,4-dimethoxytetrahydro-2H-pyran-2,5-diol-(1-4)-1,5-anhydro-3-O-methyl-2,6-di-O-sulfo-D-glucitol, ... (7 entities in total)
• Functional Keywords: serine proteinase inhibitor, antithrombin activation by hep anhydrothrombin, protein-protein interactions, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 85957.52

Authors

Dementiev, A.,Petitou, M.,Gettins, P.G. (deposition date: 2004-03-22, release date: 2004-08-17, Last modification date: 2023-08-23)

Primary citation

Dementiev, A.,Petitou, M.,Herbert, J.M.,Gettins, P.G.
The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity.
Nat.Struct.Mol.Biol., 11:863-867, 2004

PubMed Abstract: 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.

PubMed: 15311268
DOI: 10.1074/jbc.M406135200

Experimental method

X-RAY DIFFRACTION (3.1 Å)