Conformational analysis of an alpha3beta1 integrin-binding peptide from thrombospondin-1: implications for antiangiogenic drug design.

Abstract	The integrin alpha3beta1 plays important roles in development, angiogenesis, and the pathogenesis of cancer, suggesting potential therapeutic uses for antagonists of this receptor. Recently, an alpha3beta1 integrin-binding site was mapped to residues 190-201 (FQGVLQNVRFVF) of the N-terminal domain of the secreted protein thrombospondin-1 (TSP1). This sequence displays diverse biological activities in vitro and inhibits angiogenesis in vivo. Herein we describe the NMR solution conformation of this segment in both water and dodecylphosphocholine micelles. While essentially unstructured in water, a more well-defined conformation is populated in micelles, particularly in the C-terminal half of the peptide and correlated with increased biological activity of the micellar peptide. The data suggested that the residues that are critical for biological activity are contained in a structurally well-defined segment of the peptide. These data support the role of the NVR motif as a required element of full-length TSP1 for specific molecular recognition by the alpha3beta1 integrin.
Authors	Julien Furrer, Burkhard Luy, Venkatesha Basrur, David D Roberts, Joseph J Barchi Jr
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 21 Pg. 6324-33 (Oct 19 2006) ISSN: 0022-2623 [Print] United States
PMID	17034138 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References	Angiogenesis Inhibitors Integrin alpha3beta1 Micelles Oligopeptides Solutions Thrombospondin 1 Water Phosphorylcholine dodecylphosphocholine
Topics	Angiogenesis Inhibitors (chemical synthesis, chemistry, metabolism) Cell Adhesion Cell Line, Tumor Circular Dichroism Drug Design Humans Integrin alpha3beta1 (chemistry) Magnetic Resonance Spectroscopy Micelles Models, Molecular Oligopeptides (chemical synthesis, chemistry, metabolism) Phosphorylcholine (analogs & derivatives) Protein Structure, Secondary Solutions Structure-Activity Relationship Thrombospondin 1 (chemistry) Water

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