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PDBsum entry 1xse

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1xse
Jmol
Contents
Protein chains
274 a.a. *
Ligands
NDP ×2
Waters ×349
* Residue conservation analysis
PDB id:
1xse
Name: Oxidoreductase
Title: Crystal structure of guinea pig 11beta-hydroxysteroid dehydr type 1
Structure: 11beta-hydroxysteroid dehydrogenase type 1. Chain: a, b. Fragment: catalytic domain. Engineered: yes
Source: Cavia porcellus. Domestic guinea pig. Organism_taxid: 10141. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.196     R-free:   0.267
Authors: D.Ogg,B.Elleby,C.Norstrom,K.Stefansson,L.Abrahmsen,U.Opperma S.Svensson
Key ref:
D.Ogg et al. (2005). The crystal structure of guinea pig 11beta-hydroxysteroid dehydrogenase type 1 provides a model for enzyme-lipid bilayer interactions. J Biol Chem, 280, 3789-3794. PubMed id: 15542590 DOI: 10.1074/jbc.M412463200
Date:
19-Oct-04     Release date:   16-Nov-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q6QLL4  (DHI1_CAVPO) -  Corticosteroid 11-beta-dehydrogenase isozyme 1
Seq:
Struc:
300 a.a.
274 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: 10.1074/jbc.M412463200 J Biol Chem 280:3789-3794 (2005)
PubMed id: 15542590  
 
 
The crystal structure of guinea pig 11beta-hydroxysteroid dehydrogenase type 1 provides a model for enzyme-lipid bilayer interactions.
D.Ogg, B.Elleby, C.Norström, K.Stefansson, L.Abrahmsén, U.Oppermann, S.Svensson.
 
  ABSTRACT  
 
The metabolic reduction of 11-keto groups in glucocorticoid steroids such as cortisone leads to the nuclear receptor ligand cortisol. This conversion is an example of pre-receptor regulation and constitutes a novel pharmacological target for the treatment of metabolic disorders such as insulin resistance and possibly other derangements observed in the metabolic syndrome, such as hyperlipidemia, hypertension, and lowered insulin secretion. This reaction is carried out by the NADPH-dependent type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1), an enzyme attached through an integral N-terminal transmembrane helix to the lipid bilayer and located with its active site within the lumen of the endoplasmic reticulum. Here we report the crystal structure of recombinant guinea pig 11beta-HSD1. This variant was determined in complex with NADP at 2.5 A resolution and crystallized in the presence of detergent and guanidinium hydrochloride. The overall structure of guinea pig 11beta-HSD1 shows a clear relationship to other members of the superfamily of short-chain dehydrogenases/reductases but harbors a unique C-terminal helical segment that fulfills three essential functions and accordingly is involved in subunit interactions, contributes to active site architecture, and is necessary for lipid-membrane interactions. The structure provides a model for enzyme-lipid bilayer interactions and suggests a funneling of lipophilic substrates such as steroid hormones from the hydrophobic membrane environment to the enzyme active site.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Structural organization of the guinea pig 11 -HSD1 subunit. A ribbons representation of the 11 -HSD1 with secondary structural elements annotated is shown. The subunit interface is formed by helices F/ 2 and segments V3/V6/ 3 of the two monomers. Segments with low sequence identity between orthologues are shown in red (V1-V6). The guinea pig orthologue-specific C-terminal extension is shown in purple. Selected parts of the second subunit are shown in light gray and pink (V3 and V6). NADP is in ball-and-stick representation with carbon, oxygen, nitrogen, and phosphor atoms colored in green, red, blue, and purple, respectively.
Figure 4.
FIG. 4. Model of 11 -HSD1 positioning in the lipid membrane. A ribbon representation of the guinea pig 11 -HSD1 dimer with modeled transmembrane segments, showing suggested orientation in the membrane bilayer (cyan), is shown. The substrate binding site and entrance for one subunit is shown in red.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 3789-3794) copyright 2005.  
  Figures were selected by the author.  

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
20358345 M.E.Altuna, M.B.Mazzetti, L.F.Rago, L.C.San Martín de Viale, and M.C.Damasco (2009).
Hepatic 11 beta-hydroxysteroid dehydrogenase 1 involvement in alterations of glucose metabolism produced by acidotic stress in rat.
  J Physiol Biochem, 65, 329-337.  
17075950 B.D.Charette, R.G.Macdonald, S.Wetzel, D.B.Berkowitz, and H.Waldmann (2006).
Protein structure similarity clustering: dynamic treatment of PDB structures facilitates clustering.
  Angew Chem Int Ed Engl, 45, 7766-7770.  
16783599 L.Miguet, Z.Zhang, M.Barbier, and M.G.Grigorov (2006).
Comparison of a homology model and the crystallographic structure of human 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in a structure-based identification of inhibitors.
  J Comput Aided Mol Des, 20, 67-81.  
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.