Structure and protein design of a human platelet function inhibitor

Jiayin Dai, Jie Liu, Yiqun Deng, Thomas M. Smith, Min Lu

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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 β 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.

Original languageEnglish (US)
Pages (from-to)649-659
Number of pages11
JournalCell
Volume116
Issue number5
DOIs
StatePublished - Mar 5 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

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