THE 2.6-ANGSTROM STRUCTURE OF ANTITHROMBIN INDICATES A CONFORMATIONALCHANGE AT THE HEPARIN-BINDING SITE

The crystal structure of a dimeric form of intact antithrombin has bee n solved to 2.6 Angstrom, representing the highest-resolution structur e of an active, inhibitory serpin to date. The crystals were grown und er microgravity conditions on Space Shuttle mission STS-67. The overal l confidence in the structure, determined earlier from lower resolutio n data, is increased and new insights into the structure-function rela tionship are gained. Clear and continuous electron density is present for the reactive centre loop region P12 to P14 inserting into the top of the A-beta-sheet. Areas of the extended amino terminus, unique to a ntithrombin and important in the binding of the glycosaminoglycan hepa rin, can now be traced further than in the earlier structures. As in t he earlier studies, the crystals contain one active and one latent mol ecule per asymmetric unit. Better definition of the electron density s urrounding the D-helix and of the residues implicated in the binding o f the heparin pentasaccharide (Arg47, Lys114, Lys125, Arg129) provides an insight into the change of affinity of binding that accompanies th e change in conformation. In particular, the observed hydrogen bonding of these residues to the body of the molecule in the latent form expl ains the mechanism for the release of newly formed antithrombin-protea se complexes into the circulation for catabolic removal. (C) 1997 Acad emic Press Limited.