Ribbon depictions of current crystallographic structures of antithrombin showing the sequential conformational changes in antithrombin leading to the exacerbation of loss of inhibitory activity by dimerization. (A) Initiation by irreversible transition from 5-stranded (β-sheet A) active antithrombin (left), with insertion of the reactive site loop (red), to give the inactive 6-stranded latent form (right). The transition is accelerated at increased body temperature particularly in the presence of conformationally destabilizing mutations. Apposition of the 2 forms, as shown, results in the induction of β-strand conformation in the reactive site loop of the active inhibitory molecule with immediate linkage to the vacated strand in the C-sheet of the latent molecule. (B) The absence of a carbohydrate sidechain at Asn135 in β-antithrombin (β - - -) at the interface of the 2 molecules explains the preferential linkage by the latent molecule to the β-isoform. The radius of the negatively charged carbohydrate is indicated in red on the latent molecule. (C) The crystallographic (charge-contour) structure of the dimer complexed with the core pentasaccharide of heparin (green) demonstrates how full-length heparin (modelled yellow) can link the 2 molecules through a continuous cationic (blue) site to stabilize the dimer. Crystal structures shown are of dimers of latent and -antithrombin (PDB 1ant, 2ant) at 2.6Å and complexed with heparin pentasaccharide at 2.9Å (PDB 1aZx) plus the completed (but awaiting publication) structure of dimeric β-antithrombin at 2.6Å. (Figures were prepared by T.R. Dafforn, A.M. Lesk, and L. Jin, using MOLSCRIPT34 and GRASP.35 Figures are adapted and reprinted from Current Opinion in Structural Biology, Volume 8, R. W. Carrell and B. Gooptu, Conformational changes and disease—Including Serpins, Prions, and Alzheimer’s, page 799, Copyright 1998, with permission from Elsevier Science.27)