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Structure of a specific peptide complex of the carboxy‐terminal SH2 domain from the p85 alpha subunit of phosphatidylinositol 3‐kinase.
Author(s) -
Breeze A. L.,
Kara B. V.,
Barratt D. G.,
Anderson M.,
Smith J. C.,
Luke R. W.,
Best J. R.,
Cartlidge S. A.
Publication year - 1996
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1996.tb00727.x
Subject(s) - biology , phosphatidylinositol , protein subunit , sh2 domain , peptide , alpha (finance) , kinase , microbiology and biotechnology , biochemistry , peptide sequence , g alpha subunit , domain (mathematical analysis) , proto oncogene tyrosine protein kinase src , gene , medicine , mathematical analysis , construct validity , nursing , mathematics , patient satisfaction
We have determined the solution structure of the C‐terminal SH2 domain of the p85 alpha subunit of human phosphatidylinositol (PI) 3‐kinase (EC 2.7.1.137) in complex with a phosphorylated tyrosine pentapeptide sequence from the platelet‐derived growth factor receptor using heteronuclear nuclear magnetic resonance spectroscopy. Overall, the structure is similar to other SH2 domain complexes, but displays different detail interactions within the phosphotyrosine binding site and in the recognition site for the +3 methionine residue of the peptide, the side chain of which inserts into a particularly deep and narrow pocket which is displaced relative to that of other SH2 domains. The contacts made within this +3 pocket provide the structural basis for the strong selection for methionine at this position which characterizes the SH2 domains of PI3‐kinase. Comparison with spectral and structural features of the uncomplexed domain shows that the long BG loop becomes less mobile in the presence of the bound peptide. In contrast, extreme resonance broadening encountered for most residues in the beta D’, beta E and beta F strands and associated connecting loops of the domain in the absence of peptide persists in the complex, implying conformational averaging in this part of the molecule on a microsecond‐to‐millisecond time scale.