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PDBsum entry 3d3e
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Oxidoreductase
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PDB id
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3d3e
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Contents |
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* Residue conservation analysis
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Crystal structure of human 11-beta-hydroxysteroid dehydrogenase (hsd1) in complex with benzamide inhibitor
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Structure:
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Corticosteroid 11-beta-dehydrogenase isozyme 1. Chain: a, b, c, d. Synonym: 11-dh, 11-beta-hydroxysteroid dehydrogenase 1, 11-beta-hsd1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: hsd11b1, hsd11, hsd11l. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.60Å
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R-factor:
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0.230
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R-free:
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0.283
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Authors:
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Z.Wang,A.Sudom,J.Liu,N.P.Walker
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Key ref:
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L.D.Julian
et al.
(2008).
Discovery of novel, potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model.
J Med Chem,
51,
3953-3960.
PubMed id:
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Date:
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09-May-08
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Release date:
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01-Jul-08
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PROCHECK
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Headers
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References
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P28845
(DHI1_HUMAN) -
11-beta-hydroxysteroid dehydrogenase 1 from Homo sapiens
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Seq:
Struc:
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292 a.a.
262 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 4 residue positions (black
crosses)
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Enzyme class 1:
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E.C.1.1.1.146
- 11beta-hydroxysteroid dehydrogenase.
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Reaction:
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an 11beta-hydroxysteroid + NADP+ = an 11-oxosteroid + NADPH + H+
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11beta-hydroxysteroid
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+
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NADP(+)
Bound ligand (Het Group name = )
corresponds exactly
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=
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11-oxosteroid
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+
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NADPH
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+
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H(+)
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Enzyme class 2:
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E.C.1.1.1.201
- 7beta-hydroxysteroid dehydrogenase (NADP(+)).
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Reaction:
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a 7beta-hydroxysteroid + NADP+ = a 7-oxosteroid + NADPH + H+
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7beta-hydroxysteroid
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+
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NADP(+)
Bound ligand (Het Group name = )
corresponds exactly
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=
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7-oxosteroid
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+
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NADPH
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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J Med Chem
51:3953-3960
(2008)
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PubMed id:
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Discovery of novel, potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model.
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L.D.Julian,
Z.Wang,
T.Bostick,
S.Caille,
R.Choi,
M.DeGraffenreid,
Y.Di,
X.He,
R.W.Hungate,
J.C.Jaen,
J.Liu,
M.Monshouwer,
D.McMinn,
Y.Rew,
A.Sudom,
D.Sun,
H.Tu,
S.Ursu,
N.Walker,
X.Yan,
Q.Ye,
J.P.Powers.
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ABSTRACT
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We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid
dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in
vivo metabolic stability will be described. Through modifications to our initial
lead 2, we discovered pyridyl compound 13. This compound has a favorable
pharmacokinetic profile across three species and showed a dose-dependent
decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic
model.
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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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A.Vulpetti,
N.Schiering,
and
C.Dalvit
(2010).
Combined use of computational chemistry, NMR screening, and X-ray crystallography for identification and characterization of fluorophilic protein environments.
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Proteins,
78,
3281-3291.
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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
