(A) Crystallographic structures15,39,42 of antithrombin (I) and its latent form (II) in a schematic ribbon depiction illustrating the mousetrap-like mechanism of inhibition. The reactive center loop of the native molecule (blue with Arg393 as ball and stick model) can spontaneously insert as shown here as the middle strand of the A-sheet (magenta) to give the inactive but stable latent conformation. The region critical to sheet opening is indicated by the arrow in I. (B) Stereo outline showing a side view of the region underlying the opening of the A-sheet of antithrombin as arrowed in (A-I). The position of amino acids known, from other mutants,10,36 to affect the stability of sheet movement are shown as circles. Filled in blue is threonine 85 (59 in α₁-antitrypsin), the site of the Wibble and Wobble mutations. The nature of amino acid mutations at this site and their effect on stability are indicated in the side diagram. (C) Crystallographic depictions of the structure of antithrombin15 before (I) and after (II) activation by the heparin pentasaccharide, with (III) the fully activated archetypal conformation of ₁-antitrypsin.43 The structures show the sequential rearrangements involved in activation with closure of the 5-stranded A-sheet and exposure of the side chain of the reactive center. Identified constraints that hold the molecule in its low-activity (circulating) form are numbered in I. 1, the insertion of the hinge of the loop into the A-sheet; 2, the hydrogen bonding of the reactive center arginine to the body of the molecule; and 3, the stability of the semi-opened A-sheet, (Adapted and reprinted with permission from Jin et al.15 Copyright 1997 National Academy of Sciences, U.S.A.)