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PDBsum entry 1xu9

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1xu9
Jmol
Contents
Protein chains
269 a.a. *
Ligands
NDP ×4
CPS ×4
MES
Waters ×1259
* Residue conservation analysis
PDB id:
1xu9
Name: Oxidoreductase
Title: Crystal structure of the interface closed conformation of 11b-hydroxysteroid dehydrogenase isozyme 1
Structure: 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
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hsd11b1, hsd11, hsd11l. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
Resolution:
1.55Å     R-factor:   0.158     R-free:   0.181
Authors: D.J.Hosfield,Y.Wu,R.J.Skene,M.Hilger,A.Jennings,G.P.Snell, K.Aertgeerts
Key ref:
D.J.Hosfield et al. (2005). Conformational flexibility in crystal structures of human 11beta-hydroxysteroid dehydrogenase type I provide insights into glucocorticoid interconversion and enzyme regulation. J Biol Chem, 280, 4639-4648. PubMed id: 15513927 DOI: 10.1074/jbc.M411104200
Date:
25-Oct-04     Release date:   02-Nov-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P28845  (DHI1_HUMAN) -  Corticosteroid 11-beta-dehydrogenase isozyme 1
Seq:
Struc:
292 a.a.
269 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 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   7 terms 
  Biochemical function     oxidoreductase activity     3 terms  

 

 
    Added reference    
 
 
DOI no: 10.1074/jbc.M411104200 J Biol Chem 280:4639-4648 (2005)
PubMed id: 15513927  
 
 
Conformational flexibility in crystal structures of human 11beta-hydroxysteroid dehydrogenase type I provide insights into glucocorticoid interconversion and enzyme regulation.
D.J.Hosfield, Y.Wu, R.J.Skene, M.Hilgers, A.Jennings, G.P.Snell, K.Aertgeerts.
 
  ABSTRACT  
 
Human 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) is an ER-localized membrane protein that catalyzes the interconversion of cortisone and cortisol. In adipose tissue, excessive cortisol production through 11beta-HSD1 activity has been implicated in the pathogenesis of type II diabetes and obesity. We report here biophysical, kinetic, mutagenesis, and structural data on two ternary complexes of 11beta-HSD1. The combined results reveal flexible active site interactions relevant to glucocorticoid recognition and demonstrate how four 11beta-HSD1 C termini converge to form an as yet uncharacterized tetramerization motif. A C-terminal Pro-Cys motif is localized at the center of the tetramer and forms reversible enzyme disulfides that alter enzyme activity. Conformational flexibility at the tetramerization interface is coupled to structural changes at the enzyme active site suggesting how the central Pro-Cys motif may regulate enzyme activity. Together, the crystallographic and biophysical data provide a structural framework for understanding 11beta-HSD1 activities and will ultimately facilitate the development of specific inhibitors.
 
  Selected figure(s)  
 
Figure 4.
FIG. 4. Structure-based model for cortisol interactions. Illustration showing modeled cortisol (green) interactions with NADP+ (yellow) and the enzyme active site (silver). Our structure-based model predicts that the steroid D-ring deeply penetrates the enzyme active site.
Figure 6.
FIG. 6. Structure-based model for membrane interactions and subunit assembly in the ER lumen. a, schematic illustrating interactions with a single membrane within the ER lumen. Four N-terminal transmembrane helices (orange) anchor the interface-closed and interface-open tetramers (blue subunits, black C-terminal helices) to the membrane. One end of the tetramerization interface faces the membrane and one the interior of the ER lumen. The hydrophobic channel observed in the interface open structure would facilitate substrate diffusion directly from the membrane to the active sites. Trp263 and Tyr280 are represented as purple and yellow hexagons, respectively. In our dimer model for membrane association, the enzyme is anchored to the bilayer by its N-terminal transmembrane helices as well as through hydrophobic residues on the enzyme C terminus. b, schematic illustrating interactions with two closely spaced membranes within the ER lumen. The highly invaginated membrane structure of this cellular compartment suggest such interactions may be relevant in cells.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 4639-4648) 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.  
20020184 S.Ohno, M.Ohta, Y.Honda, and S.Nakajin (2010).
Sequence and expression of 11beta-hydroxysteroid dehydrogenase type 1 cDNA cloned from pig testis.
  Mol Cell Biochem, 338, 149-156.  
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.  
18175326 A.Yamamura, T.Ichimura, F.Mimoto, J.Ohtsuka, K.Miyazono, M.Okai, M.Kamo, W.C.Lee, K.Nagata, and M.Tanokura (2008).
A unique catalytic triad revealed by the crystal structure of APE0912, a short-chain dehydrogenase/reductase family protein from Aeropyrum pernix K1.
  Proteins, 70, 1640-1645.
PDB code: 2z1n
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
18388900 M.J.Lee, S.K.Fried, S.S.Mundt, Y.Wang, S.Sullivan, A.Stefanni, B.L.Daugherty, and A.Hermanowski-Vosatka (2008).
Depot-specific regulation of the conversion of cortisone to cortisol in human adipose tissue.
  Obesity (Silver Spring), 16, 1178-1185.  
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.  
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.