title: Biological implications of a 3 A structure of dimeric antithrombin.
abstract: BACKGROUND
  Antithrombin, a member of the serpin family of inhibitors, controls coagulation in human plasma by forming complexes with thrombin and other coagulation proteases in a process greatly accelerated by heparin. The structures of several serpins have been determined but not in their active conformations. We have determined the structure of intact antithrombin in order to study its mechanism of activation, particularly with respect to heparin, and the dysfunctions of this mechanism that predispose individuals to thrombotic disease.
  
  
  RESULTS
  The crystal structure of a dimer of one active and one inactive molecule of antithrombin has been determined at 3 A. The first molecule has its reactive-centre loop in a predicted active conformation compatible with initial entry of two residues into the main beta-sheet of the molecule. The inactive molecule has a totally incorporated loop as in latent plasminogen activator inhibitor-1. The two molecules are linked by the reactive loop of the active molecule which has replaced a strand from another beta-sheet in the latent molecule.
  
  
  CONCLUSIONS
  The structure, together with identified mutations affecting its heparin affinity, allows the placement of the heparin-binding site on the molecule. The conformation of the two forms of antithrombin demonstrates the extraordinary mobility of the reactive loop in the serpins and provides insights into the folding of the loop required for inhibitory activity together with the potential modification of this by heparin. The mechanism of dimerization is relevant to the polymerization that is observed in diseases associated with variant serpins.
authors.affiliation: Department of Haematology, University of Cambridge, UK.
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
authors.forename: P E
authors.initials: PE
authors.lastname: Stein
authors.forename: G
authors.initials: G
authors.lastname: Fermi
authors.forename: M R
authors.initials: MR
authors.lastname: Wardell
mesh_terms: D000595:Amino Acid Sequence; D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
chemical_list: D000991:Antithrombins; D006493:Heparin; D012697:Serine Endopeptidases; D013917:Thrombin