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PDBsum entry 2ws7
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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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PDB id:
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Hormone
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Title:
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Semi-synthetic analogue of human insulin prob26-dti
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Structure:
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Insulin a chain. Chain: a, c, e, g, i, k. Engineered: yes. Insulin b chain. Chain: b, d, f, h, j, l. Fragment: residues 25-50. Engineered: yes. Mutation: yes
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Source:
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Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606
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Resolution:
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2.59Å
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R-factor:
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0.214
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R-free:
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0.332
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Authors:
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A.M.Brzozowski,J.Jiracek,L.Zakova,E.Antolikova,C.J.Watson, J.P.Turkenburg,G.G.Dodson
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Key ref:
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J.Jirácek
et al.
(2010).
Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues.
Proc Natl Acad Sci U S A,
107,
1966-1970.
PubMed id:
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Date:
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03-Sep-09
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Release date:
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09-Feb-10
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PROCHECK
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Headers
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References
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
20 a.a.
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
19 a.a.
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
21 a.a.
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
23 a.a.
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
20 a.a.
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
20 a.a.
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
26 a.a.*
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P01308
(INS_HUMAN) -
Insulin from Homo sapiens
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Seq:
Struc:
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110 a.a.
21 a.a.
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Proc Natl Acad Sci U S A
107:1966-1970
(2010)
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PubMed id:
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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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J.Jirácek,
L.Záková,
E.Antolíková,
C.J.Watson,
J.P.Turkenburg,
G.G.Dodson,
A.M.Brzozowski.
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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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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,
and
M.C.Lawrence
(2013).
How insulin engages its primary binding site on the insulin receptor.
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Nature,
493,
241-245.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
