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Blood, 22 October 2009, Vol. 114, No. 17, pp. 3662-3667. Prepublished online as a Blood First Edition Paper on June 15, 2009; DOI 10.1182/blood-2009-04-210021. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-04-210021v1 114/17/3662    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Wei, Z. Articles by Zhou, A. PubMed PubMed Citation Articles by Wei, Z. Articles by Zhou, A. Related Collections Thrombosis and Hemostasis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Crystal structure of protein Z–dependent inhibitor complex shows how protein Z functions as a cofactor in the membrane inhibition of factor X Zhenquan Wei1,*, Yahui Yan1,*, Robin W. Carrell1, and Aiwu Zhou1 1 Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom Protein Z (PZ) binds to PZ-dependent inhibitor (ZPI) and accelerates the inhibition of the coagulation protease, activated factor X (FXa), in the presence of phospholipids and Ca2+. A 2.3Å resolution crystal structure of PZ complexed with ZPI shows that ZPI is a typical serine protease inhibitor and that PZ has a serine protease fold with distorted oxyanion hole and S1 pocket. The 2 molecules bind with fully complementary surfaces spanning over 2400Å2 and involving extensive ionic and hydrophobic interactions. ZPI has an unusual shutter region with a negatively charged residue buried within the hydrophobic core of the molecule. This unique Asp213 is critical in maintaining the balanced metastability required for optimal protease inhibition, especially when PZ is bound, with its replacement with Asn resulting in increased thermal stability, but decreased efficiency of protease inhibition. The structure of ZPI shows negatively and positively charged surfaces on top of the molecule, in keeping with mutagenesis studies in this work indicating exosite interactions with FXa when it docks on top of ZPI. As modeled in this study, the -carboxy-glutamic acid-containing domains of PZ and FXa enable them to bind to the same phospholipid surfaces on platelet and other membranes, with optimal proximity for the inhibition of FXa by the complexed ZPI. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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