Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin

James C. Whisstock, Robert N. Pike, Lei Jin, Richard Skinner, Xue Y. Pei, Robin W. Carrell, Arthur M. Lesk

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Antithrombin, uniquely among plasma serpins acting as proteinase inhibitors in the control of the blood coagulation cascade, circulates in a relatively inactive form. Its activation by heparin, and specifically by a pentasaccharide core of heparin, has been shown to involve release of the peptide loop containing the reactive centre from partial insertion in the A sheet of the molecule. Here we compare the structures of the circulating inactive form of antithrombin with the activated structure in complex with heparin pentasaccharide. We show that the rearrangement of the reactive centre loop that occurs upon activation is part of a widespread conformational change involving a realignment of the two major domains of the molecule. We also examine natural mutants that possess high affinity for heparin pentasaccharide, and relate the kinetics of their interaction with heparin pentasaccharide to the structural transitions occuring in the activation process. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)1287-1305
Number of pages19
JournalJournal of Molecular Biology
Volume301
Issue number5
DOIs
StatePublished - Sep 1 2000

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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