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PDBsum entry 3w11
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Hormone/hormone receptor/immune system
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PDB id
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3w11
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Contents |
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21 a.a.
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15 a.a.
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118 a.a.
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114 a.a.
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288 a.a.
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11 a.a.
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References listed in PDB file
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Key reference
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Title
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How insulin engages its primary binding site on the insulin receptor.
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Authors
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J.G.Menting,
J.Whittaker,
M.B.Margetts,
L.J.Whittaker,
G.K.Kong,
B.J.Smith,
C.J.Watson,
L.Záková,
E.Kletvíková,
J.Jiráček,
S.J.Chan,
D.F.Steiner,
G.G.Dodson,
A.M.Brzozowski,
M.A.Weiss,
C.W.Ward,
M.C.Lawrence.
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Ref.
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Nature, 2013,
493,
241-245.
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PubMed id
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Abstract
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Insulin receptor signalling has a central role in mammalian biology, regulating
cellular metabolism, growth, division, differentiation and survival. Insulin
resistance contributes to the pathogenesis of type 2 diabetes mellitus and the
onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers,
exacerbated by cross-talk with the homologous type 1 insulin-like growth factor
receptor (IGF1R). Despite more than three decades of investigation, the
three-dimensional structure of the insulin-insulin receptor complex has proved
elusive, confounded by the complexity of producing the receptor protein. Here we
present the first view, to our knowledge, of the interaction of insulin with its
primary binding site on the insulin receptor, on the basis of four crystal
structures of insulin bound to truncated insulin receptor constructs. The direct
interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin
receptor is seen to be sparse, the hormone instead engaging the insulin receptor
carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face
of L1 upon insulin binding. Contact between insulin and L1 is restricted to
insulin B-chain residues. The αCT segment displaces the B-chain C-terminal
β-strand away from the hormone core, revealing the mechanism of a long-proposed
conformational switch in insulin upon receptor engagement. This mode of
hormone-receptor recognition is novel within the broader family of receptor
tyrosine kinases. We support these findings by photo-crosslinking data that
place the suggested interactions into the context of the holoreceptor and by
isothermal titration calorimetry data that dissect the hormone-insulin receptor
interface. Together, our findings provide an explanation for a wealth of
biochemical data from the insulin receptor and IGF1R systems relevant to the
design of therapeutic insulin analogues.
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