Jt. Nguyen et al., Exploiting the basis of proline recognition by SH3 and WW domains: Design of n-substituted inhibitors, SCIENCE, 282(5396), 1998, pp. 2088-2092
Src homology 3 (SH3) and WW protein interaction domains bind specific proli
ne-rich sequences. However, instead of recognizing critical prolines on the
basis of side chain shape or rigidity, these domains broadly accepted amid
e N-substituted residues. Proline is apparently specifically selected in vi
vo, despite Low complementarity, because it is the only endogenous N-substi
tuted 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: scre
ening a series of Ligands in which key prolines were replaced by nonnatural
N-substituted residues yielded a Ligand that selectively bound the Grb2 SH
3 domain with 100 times greater affinity.