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PDBsum entry 1jqh
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure of bisphosphorylated igf-1 receptor kinase: insight into domain movements upon kinase activation.
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Authors
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A.Pautsch,
A.Zoephel,
H.Ahorn,
W.Spevak,
R.Hauptmann,
H.Nar.
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Ref.
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Structure, 2001,
9,
955-965.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: The insulin-like growth-factor-1 (IGF-1) receptor, which is widely
expressed in cells that have undergone oncogenic transformation, is emerging as
a novel target in cancer therapy. IGF-1-induced receptor activation results in
autophosphorylation of cytoplasmic kinase domains and enhances their capability
to phosphorylate downstream substrates. Structures of the homologous insulin
receptor kinase (IRK) exist in an open, unphosphorylated form and a closed,
trisphosphorylated form. RESULTS: We have determined the 2.1 A crystal structure
of the IGF-1 receptor protein tyrosine kinase domain phosphorylated at two
tyrosine residues within the activation loop (IGF-1RK2P) and bound to an ATP
analog. The ligand is not in a conformation compatible with phosphoryl transfer,
and the activation loop is partially disordered. Compared to the homologous
insulin receptor kinase, IGF-1RK2P is trapped in a half-closed, previously
unobserved conformation. Observed domain movements can be dissected into two
orthogonal rotational components. CONCLUSIONS: Conformational changes upon
kinase activation are triggered by the degree of phosphorylation and are
crucially dependent on the conformation of the proximal end of the kinase
activation loop. This IGF-1RK structure will provide a molecular basis for the
design of selective antioncogenic therapeutic agents.
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Figure 5.
Figure 5. Active Center and AMP-PNP Binding(a) AMP-PNP
interactions in the active site of IGF-1RK2P. The protein is
shown as a backbone representation (the glycine-rich loop is
orange and transparent, the hinge region is magenta, the
catalytic loop is green, and the activation loop is light
yellow). Atoms are color coded by type: carbon is yellow, oxygen
is red, nitrogen is blue, sulfur is green, phosphorous is
purple, and Mg2+ is black. Water molecules are blue-green
spheres.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2001,
9,
955-965)
copyright 2001.
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