3BU3

Crystal structure of the insulin receptor kinase in complex with IRS2 KRLB peptide

Summary for 3BU3

• Entry DOI: 10.2210/pdb3bu3/pdb
• Related: 3BU5 3BU6
• Descriptor: insulin receptor subunit beta, Insulin receptor substrate 2 (3 entities in total)
• Functional Keywords: irk, krlb, irs2, insulin receptor, substrate, alternative splicing, atp-binding, carbohydrate metabolism, cleavage on pair of basic residues, diabetes mellitus, disease mutation, glycoprotein, kinase, membrane, nucleotide-binding, phosphoprotein, polymorphism, transferase, transmembrane, tyrosine-protein kinase, transducer
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P06213; Cytoplasm, cytosol: P81122
• Total number of polymer chains: 2
• Total formula weight: 36749.43

Authors

Wu, J.,Hubbard, S.R. (deposition date: 2007-12-31, release date: 2008-02-19, Last modification date: 2024-10-30)

Primary citation

Wu, J.,Tseng, Y.D.,Xu, C.F.,Neubert, T.A.,White, M.F.,Hubbard, S.R.
Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2.
Nat.Struct.Mol.Biol., 15:251-258, 2008

PubMed Abstract: Insulin receptor substrates 1 and 2 (IRS1 and -2) are crucial adaptor proteins in mediating the metabolic and mitogenic effects of insulin and insulin-like growth factor 1. These proteins consist of a pleckstrin homology domain, a phosphotyrosine binding domain and a C-terminal region containing numerous sites of tyrosine, serine and threonine phosphorylation. Previous yeast two-hybrid studies identified a region unique to IRS2, termed the kinase regulatory-loop binding (KRLB) region, which interacts with the tyrosine kinase domain of the insulin receptor. Here we present the crystal structure of the insulin receptor kinase in complex with a 15-residue peptide from the KRLB region. In the structure, this segment of IRS2 is bound in the kinase active site with Tyr628 positioned for phosphorylation. Although Tyr628 was phosphorylated by the insulin receptor, its catalytic turnover was poor, resulting in kinase inhibition. Our studies indicate that the KRLB region functions to limit tyrosine phosphorylation of IRS2.

PubMed: 18278056
DOI: 10.1038/nsmb.1388

Experimental method

X-RAY DIFFRACTION (1.65 Å)