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PDBsum entry 4ifh
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Hydrolase/hydrolase inhibitor
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PDB id
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4ifh
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of human insulin degrading enzyme (ide) in complex with compound bdm44619
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Structure:
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Insulin-degrading enzyme. Chain: a, b. Synonym: abeta-degrading protease, insulin protease, insulinase, insulysin. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ide. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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3.29Å
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R-factor:
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0.185
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R-free:
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0.224
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Authors:
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W.G.Liang,Q.Guo,R.Deprez,B.Deprez,W.Tang
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Key ref:
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R.Deprez-Poulain
et al.
(2015).
Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
Nat Commun,
6,
8250.
PubMed id:
DOI:
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Date:
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14-Dec-12
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Release date:
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18-Dec-13
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Supersedes:
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PROCHECK
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Headers
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References
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P14735
(IDE_HUMAN) -
Insulin-degrading enzyme from Homo sapiens
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Seq:
Struc:
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1019 a.a.
956 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 11 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.24.56
- insulysin.
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Reaction:
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Degradation of insulin, glucagon and other polypeptides. No action on proteins.
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Cofactor:
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Zn(2+)
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DOI no:
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Nat Commun
6:8250
(2015)
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PubMed id:
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Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
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R.Deprez-Poulain,
N.Hennuyer,
D.Bosc,
W.G.Liang,
E.Enée,
X.Marechal,
J.Charton,
J.Totobenazara,
G.Berte,
J.Jahklal,
T.Verdelet,
J.Dumont,
S.Dassonneville,
E.Woitrain,
M.Gauriot,
C.Paquet,
I.Duplan,
P.Hermant,
F.X.Cantrelle,
E.Sevin,
M.Culot,
V.Landry,
A.Herledan,
C.Piveteau,
G.Lippens,
F.Leroux,
W.J.Tang,
P.van Endert,
B.Staels,
B.Deprez.
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ABSTRACT
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Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other
bioactive peptides such as amyloid-β. Knockout and genetic studies have linked
IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading
protease, IDE is a candidate drug target in diabetes. Here we have used kinetic
target-guided synthesis to design the first catalytic site inhibitor of IDE
suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray
scattering analyses show that it locks IDE in a closed conformation. Among a
panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of
mice with BDM44768 increases insulin signalling and surprisingly impairs glucose
tolerance in an IDE-dependent manner. These results confirm that IDE is involved
in pathways that modulate short-term glucose homeostasis, but casts doubt on the
general usefulness of the inhibition of IDE catalytic activity to treat diabetes.
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Links
