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PDBsum entry 4oga
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Hormone receptor/hormone/immune system
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PDB id
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4oga
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Contents |
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21 a.a.
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21 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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15 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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Protective hinge in insulin opens to enable its receptor engagement.
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Authors
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J.G.Menting,
Y.Yang,
S.J.Chan,
N.B.Phillips,
B.J.Smith,
J.Whittaker,
N.P.Wickramasinghe,
L.J.Whittaker,
V.Pandyarajan,
Z.L.Wan,
S.P.Yadav,
J.M.Carroll,
N.Strokes,
C.T.Roberts,
F.Ismail-Beigi,
W.Milewski,
D.F.Steiner,
V.S.Chauhan,
C.W.Ward,
M.A.Weiss,
M.C.Lawrence.
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Ref.
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Proc Natl Acad Sci U S A, 2014,
111,
E3395.
[DOI no: ]
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PubMed id
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Abstract
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Insulin provides a classical model of a globular protein, yet how the hormone
changes conformation to engage its receptor has long been enigmatic. Interest
has focused on the C-terminal B-chain segment, critical for protective
self-assembly in β cells and receptor binding at target tissues. Insight may be
obtained from truncated "microreceptors" that reconstitute the primary
hormone-binding site (α-subunit domains L1 and αCT). We demonstrate that, on
microreceptor binding, this segment undergoes concerted hinge-like rotation at
its B20-B23 β-turn, coupling reorientation of Phe(B24) to a 60° rotation of
the B25-B28 β-strand away from the hormone core to lie antiparallel to the
receptor's L1-β2 sheet. Opening of this hinge enables conserved nonpolar side
chains (Ile(A2), Val(A3), Val(B12), Phe(B24), and Phe(B25)) to engage the
receptor. Restraining the hinge by nonstandard mutagenesis preserves native
folding but blocks receptor binding, whereas its engineered opening maintains
activity at the price of protein instability and nonnative aggregation. Our
findings rationalize properties of clinical mutations in the insulin family and
provide a previously unidentified foundation for designing therapeutic analogs.
We envisage that a switch between free and receptor-bound conformations of
insulin evolved as a solution to conflicting structural determinants of
biosynthesis and function.
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