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Science 11 December 1998:
Vol. 282. no. 5396, pp. 2088 - 2092
DOI: 10.1126/science.282.5396.2088
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Reports

Exploiting the Basis of Proline Recognition by SH3 and WW Domains: Design of N-Substituted Inhibitors

Jack T. Nguyen, Christoph W. Turck, Fred E. Cohen, Ronald N. Zuckermann, Wendell A. Lim *

Src homology 3 (SH3) and WW protein interaction domains bind specific proline-rich sequences. However, instead of recognizing critical prolines on the basis of side chain shape or rigidity, these domains broadly accepted amide N-substituted residues. Proline is apparently specifically selected in vivo, despite low complementarity, because it is the only endogenous N-substituted amino acid. This discriminatory mechanism explains how these domains achieve specific but low-affinity recognition, a property that is necessary for transient signaling interactions. The mechanism can be exploited: screening a series of ligands in which key prolines were replaced by nonnatural N-substituted residues yielded a ligand that selectively bound the Grb2 SH3 domain with 100 times greater affinity.

J. T. Nguyen, F. E. Cohen, W. A. Lim, Department of Cellular and Molecular Pharmacology, Department of Biochemistry and Biophysics, and Graduate Group in Biophysics, University of California, San Francisco, CA 94143, USA. C. W. Turck, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA. R. N. Zuckermann, Chiron Corporation, Emeryville, CA 94608, USA.
*   To whom correspondence should be addressed E-mail: wlim{at}itsa.ucsf.edu

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