The anticoagulant activation of antithrombin by heparin.
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.
Jin
L
L
Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 2QH, United Kingdom.
Abrahams
J P
JP
Skinner
R
R
Petitou
M
M
Pike
R N
RN
Carrell
R W
RW
D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism*; D000990:Antithrombin III / Q000737:chemistry / Q000378:metabolism*; D001777:Blood Coagulation; D006493:Heparin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation
D000925:Anticoagulants; D000990:Antithrombin III; D006493:Heparin