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PDBsum entry 1y5m

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1y5m
Jmol
Contents
Protein chains
265 a.a. *
Ligands
SO4 ×4
NDP ×2
OCT ×2
Waters ×126
* Residue conservation analysis
PDB id:
1y5m
Name: Oxidoreductase
Title: The crystal structure of murine 11b-hydroxysteroid dehydrogenase: an important therapeutic target for diabetes
Structure: Corticosteroid 11-beta-dehydrogenase, isozyme 1. Chain: a, b. Fragment: sequence database residues 24-292. Synonym: 11-dh, 11-beta-hydroxysteroid dehydrogenase 1, 11- beta-hsd1, 11beta-hsd1a. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: hsd11b1, hsd11. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
2.30Å     R-factor:   0.219     R-free:   0.250
Authors: J.Zhang,T.D.Osslund,M.H.Plant,C.L.Clogston,R.E.Nybo,F.Xiong, J.M.Delaney,S.R.Jordan
Key ref:
J.Zhang et al. (2005). Crystal structure of murine 11 beta-hydroxysteroid dehydrogenase 1: an important therapeutic target for diabetes. Biochemistry, 44, 6948-6957. PubMed id: 15865440 DOI: 10.1021/bi047599q
Date:
02-Dec-04     Release date:   17-May-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P50172  (DHI1_MOUSE) -  Corticosteroid 11-beta-dehydrogenase isozyme 1
Seq:
Struc:
292 a.a.
265 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.146  - 11-beta-hydroxysteroid dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An 11-beta-hydroxysteroid + NADP+ = an 11-oxosteroid + NADPH
11-beta-hydroxysteroid
+
NADP(+)
Bound ligand (Het Group name = NDP)
corresponds exactly
= 11-oxosteroid
+ NADPH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   4 terms 
  Biological process     metabolic process   5 terms 
  Biochemical function     oxidoreductase activity     3 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/bi047599q Biochemistry 44:6948-6957 (2005)
PubMed id: 15865440  
 
 
Crystal structure of murine 11 beta-hydroxysteroid dehydrogenase 1: an important therapeutic target for diabetes.
J.Zhang, T.D.Osslund, M.H.Plant, C.L.Clogston, R.E.Nybo, F.Xiong, J.M.Delaney, S.R.Jordan.
 
  ABSTRACT  
 
11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of 11-dehydrocorticosterone to its active form corticosterone in rodents (or cortisone to cortisol in humans). The reductive reaction of the 11-keto to 11-hydroxyl is the pivotal switch in the activation of glucocorticoids. An excess of active glucocorticoids has been shown to play a key role in metabolic disorders such as diabetes and obesity. Therefore, 11beta-HSD1 represents an important therapeutic target for the treatment of these diseases. To facilitate the iterative design of inhibitors, we have crystallized and determined the three-dimensional structures of a binary complex of murine 11beta-HSD1 with NADP(H) to a resolution of 2.3 A and of a ternary complex with corticosterone and NADP(H) to a resolution of 3.0 A by X-ray crystallography. The enzyme forms a homodimer in the crystal and has a fold similar to those of other members of the family of short chain steroid dehydrogenases/reductases (SDRs). The structure shows a novel folding feature at the C-terminus of the enzyme. The C-terminal helix insertions provide additional dimer contacts, exert an influence on the conformations of the substrate binding loops, and present hydrophobic regions for potential membrane attachment. The structure also reveals how 11beta-HSD1 achieves its selectivity for its substrate.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21325058 A.J.Lawson, E.A.Walker, G.G.Lavery, I.J.Bujalska, B.Hughes, W.Arlt, P.M.Stewart, and J.P.Ride (2011).
Cortisone-reductase deficiency associated with heterozygous mutations in 11{beta}-hydroxysteroid dehydrogenase type 1.
  Proc Natl Acad Sci U S A, 108, 4111-4116.  
19507261 A.J.Lawson, E.A.Walker, S.A.White, T.R.Dafforn, P.M.Stewart, and J.P.Ride (2009).
Mutations of key hydrophobic surface residues of 11 beta-hydroxysteroid dehydrogenase type 1 increase solubility and monodispersity in a bacterial expression system.
  Protein Sci, 18, 1552-1563.
PDB code: 3dwf
19239478 P.W.Hadoke, J.Iqbal, and B.R.Walker (2009).
Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease.
  Br J Pharmacol, 156, 689-712.  
18069989 C.Hale, M.Véniant, Z.Wang, M.Chen, J.McCormick, R.Cupples, D.Hickman, X.Min, A.Sudom, H.Xu, G.Matsumoto, C.Fotsch, D.J.St Jean, and M.Wang (2008).
Structural characterization and pharmacodynamic effects of an orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor.
  Chem Biol Drug Des, 71, 36-44.
PDB code: 3bzu
17603894 A.L.Lomize, I.D.Pogozheva, M.A.Lomize, and H.I.Mosberg (2007).
The role of hydrophobic interactions in positioning of peripheral proteins in membranes.
  BMC Struct Biol, 7, 44.  
17593962 L.G.Nashev, C.Chandsawangbhuwana, Z.Balazs, A.G.Atanasov, B.Dick, F.J.Frey, M.E.Baker, and A.Odermatt (2007).
Hexose-6-phosphate dehydrogenase modulates 11beta-hydroxysteroid dehydrogenase type 1-dependent metabolism of 7-keto- and 7beta-hydroxy-neurosteroids.
  PLoS ONE, 2, e561.  
16790929 J.A.Sundlov, J.A.Garringer, J.M.Carney, A.S.Reger, E.J.Drake, W.L.Duax, and A.M.Gulick (2006).
Determination of the crystal structure of EntA, a 2,3-dihydro-2,3-dihydroxybenzoic acid dehydrogenase from Escherichia coli.
  Acta Crystallogr D Biol Crystallogr, 62, 734-740.
PDB code: 2fwm
16547389 T.Matsunaga, S.Shintani, and A.Hara (2006).
Multiplicity of mammalian reductases for xenobiotic carbonyl compounds.
  Drug Metab Pharmacokinet, 21, 1.  
16181035 R.Thieringer, and A.Hermanowski-Vosatka (2005).
Inhibition of 11beta-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role?
  Expert Rev Cardiovasc Ther, 3, 911-924.  
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 code is shown on the right.