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Dehydrogenase PDB id
1fdw
Jmol
Contents
Protein chain
279 a.a. *
Ligands
EST
Waters ×8
* Residue conservation analysis
PDB id:
1fdw
Name: Dehydrogenase
Title: Human 17-beta-hydroxysteroid-dehydrogenase type 1 mutant h22 complexed with estradiol
Structure: 17-beta-hydroxysteroid dehydrogenase. Chain: a. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: cytoplasm. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
2.70Å     R-factor:   0.178     R-free:   0.263
Authors: C.Mazza,R.Breton,D.Housset,J.-C.Fontecilla-Camps
Key ref:
C.Mazza et al. (1998). Unusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenase. J Biol Chem, 273, 8145-8152. PubMed id: 9525918 DOI: 10.1074/jbc.273.14.8145
Date:
16-Jan-98     Release date:   27-May-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P14061  (DHB1_HUMAN) -  Estradiol 17-beta-dehydrogenase 1
Seq:
Struc: 		328 a.a.
279 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.62  - Estradiol 17-beta-dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Estradiol-17-beta + NAD(P)(+) = estrone + NAD(P)H
Estradiol-17-beta
Bound ligand (Het Group name = EST)
corresponds exactly 		+ NAD(P)(+)
 = estrone
 + NAD(P)H
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   2 terms 
  Biological process     metabolic process   7 terms 
  Biochemical function     catalytic activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.273.14.8145 J Biol Chem 273:8145-8152 (1998)
PubMed id: 9525918  
 
 
Unusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenase.
C.Mazza, R.Breton, D.Housset, J.C.Fontecilla-Camps.
 
  ABSTRACT  
 
Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes. These structures provide a complete picture of the NADP+-enzyme interactions involving the flexible 191-199 loop (well ordered in the H221L mutant) and suggest that the hydrophobic residues Phe192-Met193 could facilitate hydride transfer. 17beta-HSD1 appears to be unique among the members of the SDR protein family in that one of the two basic residues involved in the charge compensation of the 2'-phosphate does not belong to the Rossmann-fold motif. The remarkable stabilization of the NADP+ 2'-phosphate by the enzyme also clearly establishes its preference for this cofactor relative to NAD+. Analysis of the catalytic properties of, and estradiol binding to, the two mutants suggests that the His221-steroid O3 hydrogen bond plays an important role in substrate specificity.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Superposition of the 187-209 loop of the wild-type 17 -HSD1 model (1bhs (24)) (medium gray) and the monomer mC of the H221L·E2·NAD^+ complex (black) with the 182-203 loop of the MLCR model (1cyd (22)) (light gray). Phe^192 of the H221L mutant and Met186 of MLCR superpose very well and make extensive hydrophobic contacts with the nicotinamide ring. Lys195 of the H221L model interacts with the 2'-phosphate while no equivalent residue is found for MLCR. 		Figure 6.
Fig. 6. Stereoscopic view of the steroid binding site of wild-type (1fdt model in yellow, and 1fds model in orange), H221L (monomers mC in blue, mD in light blue), and H221Q (pink). Phe^226 of the 1fdt model and Gln221 of the H221Q mutant are shown with their two modeled conformations. The steroid environment is very well conserved, especially Phe^155 and Ser142 which are the residues involved in the catalytic reaction. Significant deviations are observed for the steroid, especially for its C and D rings.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (1998, 273, 8145-8152) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21337522 A.Oster, T.Klein, C.Henn, R.Werth, S.Marchais-Oberwinkler, M.Frotscher, and R.W.Hartmann (2011).
Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β-Hydroxysteroid Dehydrogenase Type 1 (17 β-HSD1): The Role of the Bicyclic Moiety.
  ChemMedChem, 6, 476-487.  
20706575 M.Negri, M.Recanatini, and R.W.Hartmann (2010).
Insights in 17beta-HSD1 enzyme kinetics and ligand binding by dynamic motion investigation.
  PLoS One, 5, e12026.  
19929851 M.Mazumdar, D.Fournier, D.W.Zhu, C.Cadot, D.Poirier, and S.X.Lin (2009).
Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy.
  Biochem J, 424, 357-366.
PDB codes: 3hb4 3hb5
18452026 R.Machielsen, N.G.Leferink, A.Hendriks, S.J.Brouns, H.G.Hennemann, T.Dauβmann, and J.van der Oost (2008).
Laboratory evolution of Pyrococcus furiosus alcohol dehydrogenase to improve the production of (2S,5S)-hexanediol at moderate temperatures.
  Extremophiles, 12, 587-594.  
18566346 R.Zhang, G.Zhu, W.Zhang, S.Cao, X.Ou, X.Li, M.Bartlam, Y.Xu, X.C.Zhang, and Z.Rao (2008).
Crystal structure of a carbonyl reductase from Candida parapsilosis with anti-Prelog stereospecificity.
  Protein Sci, 17, 1412-1423.
PDB code: 3ctm
17958702 K.S.Paithankar, C.Feller, E.B.Kuettner, A.Keim, M.Grunow, and N.Sträter (2007).
Cosubstrate-induced dynamics of D-3-hydroxybutyrate dehydrogenase from Pseudomonas putida.
  FEBS J, 274, 5767-5779.
PDB codes: 2q2q 2q2v 2q2w
16531240 A.H.Ehrensberger, R.A.Elling, and D.K.Wilson (2006).
Structure-guided engineering of xylitol dehydrogenase cosubstrate specificity.
  Structure, 14, 567-575.
PDB code: 1zem
12524453 J.K.Yang, M.S.Park, G.S.Waldo, and S.W.Suh (2003).
Directed evolution approach to a structural genomics project: Rv2002 from Mycobacterium tuberculosis.
  Proc Natl Acad Sci U S A, 100, 455-460.
PDB codes: 1nff 1nfq 1nfr
11306082 D.Ghosh, and P.Vihko (2001).
Molecular mechanisms of estrogen recognition and 17-keto reduction by human 17beta-hydroxysteroid dehydrogenase 1.
  Chem Biol Interact, 130, 637-650.  
10707028 B.S.Zhorov, and S.X.Lin (2000).
Monte Carlo-minimized energy profile of estradiol in the ligand-binding tunnel of 17 beta-hydroxysteroid dehydrogenase: atomic mechanisms of steroid recognition.
  Proteins, 38, 414-427.  
10489462 D.G.Gourley, J.Luba, L.W.Hardy, S.M.Beverley, and W.N.Hunter (1999).
Crystallization of recombinant Leishmania major pteridine reductase 1 (PTR1).
  Acta Crystallogr D Biol Crystallogr, 55, 1608-1610.  
9927655 M.W.Sawicki, M.Erman, T.Puranen, P.Vihko, and D.Ghosh (1999).
Structure of the ternary complex of human 17beta-hydroxysteroid dehydrogenase type 1 with 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+.
  Proc Natl Acad Sci U S A, 96, 840-845.
PDB code: 1equ
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.