1oo3 Citations

Nuclear magnetic resonance structure of the P395S mutant of the N-SH2 domain of the p85 subunit of PI3 kinase: an SH2 domain with altered specificity.

Biochemistry 42 11120-7 (2003)
Cited: 2 times
EuropePMC logo PMID: 14503862

Abstract

Understanding the specificity of Src homology 2 (SH2) domains is important because of their critical role in cell signaling. Previous genetic analysis has characterized mutants of the N-terminal src homology 2 (SH2) domain of the p85 subunit of phosphoinositide 3-kinase (PI3K). The P395S mutant exhibits a specificity for phosphopeptide binding different from that of the wild-type SH2. The P395S mutant has an increased affinity for the platelet-derived growth factor receptor (PDGFr) compared to polyomavirus middle T antigen (MT). Solution structures of the P395S mutant of the p85 N-SH2 alone and complexed to a PDGFr phosphopeptide were determined to explain the change in specificity. Chemical shift perturbations caused by different peptides were compared for mutant and wild-type structures. The results show that the single P395S mutation has broad effects on the structure. Furthermore, they provide a rationale for the observed changes in binding preference.

Reviews citing this publication (1)

  1. Somatic mutations in PI3Kalpha: structural basis for enzyme activation and drug design. Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. Biochim. Biophys. Acta 1804 533-540 (2010)

Articles citing this publication (1)

  1. Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J. EMBO J. 27 804-816 (2008)