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Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes

Nature Structural Biology volume 3, pages 364–374 (1996)Cite this article

Abstract

Crystal structures of the amino-terminal SH2 domain of the p85α subunit of phosphatidylinositol (PI) 3-kinase, alone and in complex with phosphopeptides bearing pTyr-Met/Val-Xaa-Met motifs, show that phosphopeptides bind in the two-pronged manner seen in high-affinity Lck and Src SH2 complexes, with conserved interactions between the domain and the peptide segment from phosphotyrosine to Met+3. Peptide binding requires the rearrangement of a tyrosyl side chain in the BG loop to create the hydrophobic Met+3 binding pocket. The structures suggest a mechanism for the biological specificity exhibited by PI 3-kinase in its interactions with phosphoprotein partners.

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Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute and Laboratory of Molecular Medicine, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA

    R.T. Nolte, M.J. Eck & S.C. Harrison

  2. Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts, 02215, USA

    R.T. Nolte

  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA

    M.J. Eck & S.E. Shoelson

  4. Department of Pharmacology, New York University Medical Center, New York, New York, 10016, USA

    J. Schlessinger

  5. Research Division, Joslin Diabetes Center, Boston, Massachusetts, 02215, USA

    S.E. Shoelson

  6. Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, Massachusetts, 02138, USA

    S.C. Harrison

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  1. R.T. Nolte
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  4. S.E. Shoelson
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Nolte, R., Eck, M., Schlessinger, J. et al. Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat Struct Mol Biol 3, 364–374 (1996). https://doi.org/10.1038/nsb0496-364

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