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Blood, 22 January 2009, Vol. 113, No. 4, pp. 902-910. Prepublished online as a Blood First Edition Paper on November 5, 2008; DOI 10.1182/blood-2008-09-177337. This Article Full Text (PDF) All Versions of this Article: blood-2008-09-177337v1 113/4/902    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Basani, R. B Articles by Poncz, M. Search for Related Content PubMed PubMed Citation Articles by Basani, R. B Articles by Poncz, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 8, 2008 Accepted October 7, 2008 Species differences in small molecule binding to IIb3 are due to sequence differences in two loops of the IIb propeller Ramesh B Basani, Hua Zhu, Michael A Thornton, Cinque S Soto, William F DeGrado, M Anna Kowalska, Joel S Bennett, and Mortimer Poncz* Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, United States Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States Department of Biology, Florida A&M University, Tallahassee, FL, United States Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States * Corresponding author; email: poncz{at}email.chop.edu. Compared to human platelets, rodent platelets are less responsive to peptides and peptidomimetics containing an arginine-glycine-aspartic acid (RGD) motif. Using chimeric human-rat IIb3 molecules, we found that this difference in RGDS sensitivity was due to amino acid substitutions at residues 157, 159, and 162 in the W3:4-1 loop and an Asp-His replacement at residue 232 in the W4:4-1 loop of the IIb propeller. Introducing the entire rat W3:4-1 and W4:4-1 loops into human IIb3 also decreased the inhibitory effect of the disintegrins, echistatin and eristostatin, and the IIb3 antagonists, tirofiban and eptifibatide, on fibrinogen binding, whereas the specific point mutations did not. This suggests that RGDS interacts with IIb in a different manner than with these small molecules. None of these species-based substitutions affected the ability of IIb3 to interact with RGD-containing macromolecules. Thus, human von Willebrand factor (VWF) contains an RGD motif and binds equally well to ADP-stimulated human and rodent platelets, implying that other motifs are responsible for maintaining ligand binding affinity. Many venoms contain RGD-based toxins. Our data suggest that these species amino acids differences in the IIb -propeller represent an evolutionary response by rodents to maintain hemostasis, while concurrently protecting against RGD-containing toxins. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Blue, M. A. Kowalska, J. Hirsch, M. Murcia, C. A. Janczak, A. Harrington, M. Jirouskova, J. Li, R. Fuentes, M. A. Thornton, et al. Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel {alpha}IIb-specific {alpha}IIb{beta}3 antagonist Blood, July 2, 2009; 114(1): 195 - 201. [Abstract] [Full Text] [PDF]

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