1P14
Crystal structure of a catalytic-loop mutant of the insulin receptor tyrosine kinase
Summary for 1P14
Entry DOI | 10.2210/pdb1p14/pdb |
Related | 1IRK |
Descriptor | insulin receptor (2 entities in total) |
Functional Keywords | receptor, tyrosine kinase, catalysis, mutant, transferase |
Biological source | Homo sapiens (human) |
Cellular location | Membrane; Single-pass type I membrane protein: P06213 |
Total number of polymer chains | 1 |
Total formula weight | 34792.74 |
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 citation | Li, 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: 12707268DOI: 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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