Lim Lab | Papers

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, and Wendell A. Lim
Science 282, 2088-2092 (1998)

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.

Commentary in Chemistry and Biology by Behzad Aghazadeh and Michael K. Rosen