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A paradigm for drug discovery using a conformation from the crystal structure of a presentation scaffold

Nature Structural Biology volume 2, pages 1131–1137 (1995)Cite this article

Abstract

We describe a structural validation of the use of presentation scaffolds for control and elucidation of bioactive conformations of peptides. The protein REI-RGD34—produced by inserting the sequence RIPRGDMP into the CDR1 loop region of the immunoglobulin VL domain REI—strongly inhibits fibrinogen binding to the integrins αIIbβ3 and αVβ3. In the X-ray crystal structure of this protein at 2.4 Å resolution, the RGD-containing loop exhibits defined electron density that is consistent with models for the bioactive conformations of ligands of these receptors based on previous small-molecule studies. Furthermore, a search of a small- molecule database with conformational information derived from the structure of REI-RGD34 identified constrained peptides and peptidomimetics known to be antagonists of the platelet receptor αIIbβ3.

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Authors and Affiliations

  1. Departments of Macromolecular Sciences, SmithKline Beecham Pharmaceuticals, Inc., 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA

    Baoguang Zhao, Larry R. Helms, Sherin S. Abdel-Meguid & Ronald Wetzel

  2. Departments of Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, Inc., 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA

    Renee L. DesJarlais

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  1. Baoguang Zhao
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Zhao, B., Helms, L., DesJarlais, R. et al. A paradigm for drug discovery using a conformation from the crystal structure of a presentation scaffold. Nat Struct Mol Biol 2, 1131–1137 (1995). https://doi.org/10.1038/nsb1295-1131

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