PDBsum entry 3bu6

Transferase

PDB id: 3bu6

Contents

Protein chains

297 a.a. *

14 a.a. *

Waters ×213

* Residue conservation analysis

PDB id:

3bu6

Name:

Transferase

Title:

Crystal structure of the insulin receptor kinase in complex with irs2 krlb phosphopeptide

Structure:

Insulin receptor subunit beta. Chain: a. Fragment: protein kinase. Synonym: ir, cd220 antigen. Engineered: yes. Insulin receptor substrate 2. Chain: b. Fragment: unp residues 620-634. Synonym: irs-2, 4ps.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: insr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Other_details: the sequence of this peptide natually exists in mus musculus.

Resolution:

1.95Å R-factor: 0.202 R-free: 0.239

Authors:

J.Wu,S.R.Hubbard

Key ref:

J.Wu et al. (2008). Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol, 15, 251-258. PubMed id: 18278056 DOI: 10.1038/nsmb.1388

Date:

31-Dec-07 Release date: 19-Feb-08

Protein chain

P06213  (INSR_HUMAN) -  Insulin receptor from Homo sapiens

Seq: 1382 a.a.

Struc: 297 a.a.*

Protein chain

P81122  (IRS2_MOUSE) -  Insulin receptor substrate 2 from Mus musculus

Seq: 1321 a.a.

Struc: 14 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/nsmb.1388

Nat Struct Mol Biol 15:251-258 (2008)

PubMed id: 18278056

Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2.

J.Wu, Y.D.Tseng, C.F.Xu, T.A.Neubert, M.F.White, S.R.Hubbard.

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.

Selected figure(s)

Figure 1.
Domain organization and location of tyrosine-phosphorylation sites are drawn to linear scale (mouse numbering, 1,321 residues). Tyrosine-phosphorylation sites that are recruitment sites for PI3K (Y XM motif) are labeled by ^*, the GRB2 site (Y911) is labeled by † and the two SHP2 sites (Y1242 and Y1303) are labeled by §. The KRLB region as determined by Y2H studies (residues 591–733) is shown with dashed lines, and the 15-residue region that was cocrystallized with IRK is shown in the gray box, with the sequence expanded below and Tyr628 underlined. The corresponding 15-residue sequence in IRS1 (mouse) is also shown.

Figure 2.
(a) IRK is shown as a molecular surface, with the N lobe colored dark gray and the C lobe colored light gray. The activation loop (residues 1150–1171) is colored green and the catalytic loop (residues 1130–1137) is colored orange. IRS2 KRLB^Y628 is shown in stick representation. The final 2F[o] - F[c] electron density (1.65-Å resolution, 1 contour) is shown in blue mesh. The N and C termini of the peptide are labeled.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2008, 15, 251-258) copyright 2008.

Figures were selected by an automated process.