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Cell. 2004 Mar 5;116(5):649-59.

Structure and protein design of a human platelet function inhibitor.

Author information

  • 1Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA.

Erratum in

  • Cell. 2004 Apr 30;117(3):413.

Abstract

Hematophagous arthropods secrete a salivary apyrase that inhibits platelet activation by catabolizing ADP released from damaged tissues and blood cells. We report the X-ray crystal structures of a human enzyme of the soluble apyrase family in its apo state and bound to a substrate analog. The structures reveal a nucleotide binding domain comprising a five-blade beta propeller, binding determinants of the substrate and the active site, and an unusual calcium binding site with a potential regulatory function. Using a comparative structural biology approach, we were able to redesign the human apyrase so as to enhance its ADPase activity by more than 100-fold. The engineered enzyme is a potent inhibitor of platelet aggregation and may serve as the basis for the development of a new class of antithrombotic agents.

PMID:
15006348
[PubMed - indexed for MEDLINE]
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