Journal Home
Search for

Volume 583, Issue 21, Pages 3397-3400 (3 November 2009)


View previous. 4 of 27 View next.

Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement

Edited by Veli-Pekka Lehto

Peter G.W. GettinsaCorresponding Author Informationemail address, Steven T. Olsonbemail address

Received 21 July 2009; received in revised form 25 September 2009; accepted 1 October 2009. published online 08 October 2009.

Abstract 

Allosteric activation of antithrombin as a rapid inhibitor of factors IXa and Xa requires binding of a high-affinity heparin pentasaccharide. The currently-accepted mechanism involves removal of a constraint on the antithrombin reactive center loop (RCL) so that the proteinase can simultaneously engage both the P1 arginine and an exosite at Y253. Recent results suggest that this mechanism is incorrect in that activation can be achieved without loop expulsion, while the exosite can be engaged in both low and high activity states. We propose a quite different mechanism in which heparin activates antithrombin by mitigating an unfavorable surface interaction, by altering its nature, and by moving the attached proteinase away from the site of the unfavorable interaction through RCL expulsion.

a Department of Biochemistry and Molecular Genetics, and Center for Structural Biology, University of Illinois at Chicago, IL 60612-4316, USA

b Center for Molecular Biology of Oral Disease, and Center for Structural Biology, University of Illinois at Chicago, IL 60612-4316, USA

Corresponding Author InformationCorresponding author. Fax: +1 312 413 0353.

PII: S0014-5793(09)00775-3

doi:10.1016/j.febslet.2009.10.005


View previous. 4 of 27 View next.