NDLI: Binding of small molecules to an adaptive protein-protein interface.

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Binding of small molecules to an adaptive protein-protein interface.

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Binding of small molecules to an adaptive protein-protein interface.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Randal, Mike Oslob, Johan D. Raphael, Darren R. Braisted, Andrew C. Hyde, Jennifer Wells, James A. Mcdowell, Robert S. Wang, Jun Delano, Warren L. Luong, Tinh N. Taylor, Lisa Arkin, Michelle R.
Description	Author Affiliation: Arkin MR ( Department of Biology, Sunesis Pharmaceuticals, South San Francisco, CA 94080-1913, USA. mra@sunesis.com);
Abstract	Understanding binding properties at protein-protein interfaces has been limited to structural and mutational analyses of natural binding partners or small peptides identified by phage display. Here, we present a high-resolution analysis of a nonpeptidyl small molecule, previously discovered by medicinal chemistry [Tilley, J. W., et al. (1997) J. Am. Chem. Soc. 119, 7589-7590], which binds to the cytokine IL-2. The small molecule binds to the same site that binds the IL-2 alpha receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein-protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	4
Volume Number	100
Language	English
Publisher	National Academy of Sciences
Publisher Date	2003-02-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Interleukin-2 Metabolism Cloning, Molecular Crystallography, X-Ray Genetics Ligands Models, Molecular Protein Binding Receptors, Interleukin-2 Surface Plasmon Resonance Thermodynamics Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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