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PDBsum entry 2ws7
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Contents |
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20 a.a.
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19 a.a.
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21 a.a.
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23 a.a.
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20 a.a.
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20 a.a.
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26 a.a.
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21 a.a.
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19 a.a.
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21 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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Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues.
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Authors
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J.Jirácek,
L.Záková,
E.Antolíková,
C.J.Watson,
J.P.Turkenburg,
G.G.Dodson,
A.M.Brzozowski.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
1966-1970.
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PubMed id
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Abstract
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Insulin is a key protein hormone that regulates blood glucose levels and, thus,
has widespread impact on lipid and protein metabolism. Insulin action is
manifested through binding of its monomeric form to the Insulin Receptor (IR).
At present, however, our knowledge about the structural behavior of insulin is
based upon inactive, multimeric, and storage-like states. The active monomeric
structure, when in complex with the receptor, must be different as the residues
crucial for the interactions are buried within the multimeric forms. Although
the exact nature of the insulin's induced-fit is unknown, there is strong
evidence that the C-terminal part of the B-chain is a dynamic element in insulin
activation and receptor binding. Here, we present the design and analysis of
highly active (200-500%) insulin analogues that are truncated at residue 26 of
the B-chain (B(26)). They show a structural convergence in the form of a new
beta-turn at B(24)-B(26). We propose that the key element in insulin's
transition, from an inactive to an active state, may be the formation of the
beta-turn at B(24)-B(26) associated with a trans to cis isomerisation at the
B(25)-B(26) peptide bond. Here, this turn is achieved with N-methylated L-amino
acids adjacent to the trans to cis switch at the B(25)-B(26) peptide bond or by
the insertion of certain D-amino acids at B(26). The resultant conformational
changes unmask previously buried amino acids that are implicated in IR binding
and provide structural details for new approaches in rational design of ligands
effective in combating diabetes.
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