2SEM

Exploiting the basis of proline recognition by SH3 and WW domains: design of N-substituted inhibitors.

(1998) Science 282: 2088-2092

• PubMed: 9851931 Search on PubMed
• DOI: https://doi.org/10.1126/science.282.5396.2088
• Primary Citation of Related Structures:  
  1B07, 2SEM, 3SEM


• PubMed 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.

   View More

---

Organizational Affiliation: 

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.