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From Proteopedia
CRYSTAL STRUCTURE OF THE PH-PTB TARGETING REGION OF IRS-1
Structural highlights
Disease[IRS1_HUMAN] Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853].[1] [2] [3] [4] [5] Function[IRS1_HUMAN] May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).[6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedWe have determined the crystal structure at 2.3-A resolution of an amino-terminal segment of human insulin receptor substrate 1 that encompasses its pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains. Both domains adopt the canonical seven-stranded beta-sandwich PH domain fold. The domains are closely associated, with a 720-A(2) contact surface buried between them that appears to be stabilized by ionic, hydrophobic, and hydrogen bonding interactions. The nonconserved 46-residue linker between the domains is disordered. The PTB domain peptide binding site is fully exposed on the molecular surface, as is a large cationic patch at the base of the PH domain that is a likely binding site for the head groups of phosphatidylinositol phosphates. Binding assays confirm that phosphatidylinositol phosphates bind the PH domain, but not the PTB domain. Ligand binding to the PH domain does not alter PTB domain interactions, and vice versa. The structural and accompanying functional data illustrate how the two binding domains might act cooperatively to effectively increase local insulin receptor substrate 1 concentration at the membrane and transiently fix the receptor and substrate, to allow multiple phosphorylation reactions to occur during each union. Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB) targeting region of insulin receptor substrate 1.,Dhe-Paganon S, Ottinger EA, Nolte RT, Eck MJ, Shoelson SE Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8378-83. PMID:10411883[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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