1AZX

ANTITHROMBIN/PENTASACCHARIDE COMPLEX

Summary for 1AZX

• Entry DOI: 10.2210/pdb1azx/pdb
• Related PRD ID: PRD_900031
• Descriptor: ANTITHROMBIN, 3,4-di-O-methyl-2,6-di-O-sulfo-alpha-D-glucopyranose-(1-4)-2,3-di-O-methyl-beta-D-glucopyranuronic acid-(1-4)-2,3,6-tri-O-sulfo-alpha-D-glucopyranose-(1-4)-3-O-methyl-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-methyl 2,3,6-tri-O-sulfo-alpha-D-glucopyranoside, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: serine protease inhibitor, serpin, antithrombin, anticoagulant activation by heparin
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space: P01008
• Total number of polymer chains: 2
• Total formula weight: 102188.48

Authors

Jin, L.,Abrahams, J.P.,Skinner, R.,Petitou, M.,Pike, R.N.,Carrell, R.W. (deposition date: 1997-11-23, release date: 1999-01-13, Last modification date: 2024-10-30)

Primary citation

Jin, L.,Abrahams, J.P.,Skinner, R.,Petitou, M.,Pike, R.N.,Carrell, R.W.
The anticoagulant activation of antithrombin by heparin.
Proc.Natl.Acad.Sci.USA, 94:14683-14688, 1997

PubMed Abstract: Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the coagulation proteases until it binds to the heparan side chains that line the microvasculature. The binding specifically occurs to a core pentasaccharide present both in the heparans and in their therapeutic derivative heparin. The accompanying conformational change of antithrombin is revealed in a 2.9-A structure of a dimer of latent and active antithrombins, each in complex with the high-affinity pentasaccharide. Inhibitory activation results from a shift in the main sheet of the molecule from a partially six-stranded to a five-stranded form, with extrusion of the reactive center loop to give a more exposed orientation. There is a tilting and elongation of helix D with the formation of a 2-turn helix P between the C and D helices. Concomitant conformational changes at the heparin binding site explain both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin-protease complex into the circulation. The pentasaccharide binds by hydrogen bonding of its sulfates and carboxylates to Arg-129 and Lys-125 in the D-helix, to Arg-46 and Arg-47 in the A-helix, to Lys-114 and Glu-113 in the P-helix, and to Lys-11 and Arg-13 in a cleft formed by the amino terminus. This clear definition of the binding site will provide a structural basis for developing heparin analogues that are more specific toward their intended target antithrombin and therefore less likely to exhibit side effects.

PubMed: 9405673
DOI: 10.1073/pnas.94.26.14683

Experimental method

X-RAY DIFFRACTION (2.9 Å)