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1P14

Crystal structure of a catalytic-loop mutant of the insulin receptor tyrosine kinase

Summary for 1P14
Entry DOI10.2210/pdb1p14/pdb
Related1IRK
Descriptorinsulin receptor (2 entities in total)
Functional Keywordsreceptor, tyrosine kinase, catalysis, mutant, transferase
Biological sourceHomo sapiens (human)
Cellular locationMembrane; Single-pass type I membrane protein: P06213
Total number of polymer chains1
Total formula weight34792.74
Authors
Li, S.,Covino, N.D.,Stein, E.G.,Till, J.H.,Hubbard, S.R. (deposition date: 2003-04-11, release date: 2003-07-22, Last modification date: 2023-08-16)
Primary citationLi, S.,Covino, N.D.,Stein, E.G.,Till, J.H.,Hubbard, S.R.
Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor
J.Biol.Chem., 278:26007-26014, 2003
Cited by
PubMed Abstract: Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus.
PubMed: 12707268
DOI: 10.1074/jbc.M302425200
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.9 Å)
Structure validation

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