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

Science  11 Dec 1998:
Vol. 282, Issue 5396, pp. 2088-2092
DOI: 10.1126/science.282.5396.2088

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Abstract

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.

  • * To whom correspondence should be addressed E-mail: wlim{at}itsa.ucsf.edu

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