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PDBsum entry 2fgb

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Oxidoreductase PDB id
2fgb
Jmol
Contents
Protein chain
312 a.a. *
Ligands
ACT
P6G
NAP
Waters ×394
* Residue conservation analysis
PDB id:
2fgb
Name: Oxidoreductase
Title: Crystal structure of human 17bet a-hydroxysteroid dehydrogenase type 5 in complexes with peg and NADP
Structure: Aldo-keto reductase family 1 member c3. Chain: a. Synonym: trans-1,2- dihydrobenzene-1,2-diol dehydrogenase, 3-alpha- hydroxysteroid dehydrogenase type 2, 3-alpha-hsd type 2, 3-alpha-hsd type ii, brain, prostaglandin f synthase, pgfs, estradiol 17-beta-dehydrogenase, 17-beta- hydroxysteroid dehydrogenase type 5, 17-beta-hsd 5, chlordecone reductase homolog hakrb, ha1753, dihydrodiol dehydrogenase type i, dihydrodiol dehydrogenase 3, dd3, dd-
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: akr1c3, ddh1, kiaa0119, pgfs. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Monomer (from PQS)
Resolution:
1.35Å     R-factor:   0.172     R-free:   0.190
Authors: W.Qiu,M.Zhou,A.Azzi,V.Luu-The,F.Labrie,S.X.Lin
Key ref:
W.Qiu et al. (2007). Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase. J Biol Chem, 282, 8368-8379. PubMed id: 17166832 DOI: 10.1074/jbc.M606784200
Date:
21-Dec-05     Release date:   12-Dec-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P42330  (AK1C3_HUMAN) -  Aldo-keto reductase family 1 member C3
Seq:
Struc:
323 a.a.
312 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 1: E.C.1.1.1.112  - Indanol dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Indan-1-ol + NAD(P)(+) = indanone + NAD(P)H
Indan-1-ol
+
NAD(P)(+)
Bound ligand (Het Group name = NAP)
corresponds exactly
= indanone
+ NAD(P)H
   Enzyme class 2: E.C.1.1.1.188  - Prostaglandin-F synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (5Z,13E)-(15S)-9-alpha,11-alpha,15-trihydroxyprosta-5,13-dienoate + NADP+ = (5Z,13E)-(15S)-9-alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate + NADPH
(5Z,13E)-(15S)-9-alpha,11-alpha,15-trihydroxyprosta-5,13-dienoate
+
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly
= (5Z,13E)-(15S)-9-alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
+ NADPH
   Enzyme class 3: E.C.1.1.1.239  - 3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Testosterone + NAD+ = androstenedione + NADH
Testosterone
+
NAD(+)
Bound ligand (Het Group name = NAP)
corresponds exactly
= androstenedione
+ NADH
   Enzyme class 4: E.C.1.1.1.357  - 3-alpha-hydroxysteroid 3-dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A 3-alpha-hydroxysteroid + NAD(P)(+) = a 3-oxosteroid + NAD(P)H
3-alpha-hydroxysteroid
+
NAD(P)(+)
Bound ligand (Het Group name = NAP)
matches with 91.00% similarity
= 3-oxosteroid
+ NAD(P)H
   Enzyme class 5: E.C.1.1.1.64  - Testosterone 17-beta-dehydrogenase (NADP(+)).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Testosterone + NADP+ = androst-4-ene-3,17-dione + NADPH
Testosterone
+
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly
= androst-4-ene-3,17-dione
+ NADPH
   Enzyme class 6: E.C.1.3.1.20  - Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Trans-1,2-dihydrobenzene-1,2-diol + NADP+ = catechol + NADPH
Trans-1,2-dihydrobenzene-1,2-diol
+
NADP(+)
Bound ligand (Het Group name = NAP)
corresponds exactly
= catechol
+ NADPH
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.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   4 terms 
  Biological process     small molecule metabolic process   37 terms 
  Biochemical function     dihydrotestosterone 17-beta-dehydrogenase activity     21 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M606784200 J Biol Chem 282:8368-8379 (2007)
PubMed id: 17166832  
 
 
Structure-based inhibitor design for an enzyme that binds different steroids: a potent inhibitor for human type 5 17beta-hydroxysteroid dehydrogenase.
W.Qiu, M.Zhou, M.Mazumdar, A.Azzi, D.Ghanmi, V.Luu-The, F.Labrie, S.X.Lin.
 
  ABSTRACT  
 
Human type 5 17beta-hydroxysteroid dehydrogenase plays a crucial role in local androgen formation in prostate tissue. Several chemicals were synthesized and tested for their ability to inhibit this enzyme, and a series of estradiol derivatives bearing a lactone on the D-ring were found to inhibit its activity efficiently. The crystal structure of the type 5 enzyme in complex with NADP and such a novel inhibitor, EM1404, was determined to a resolution of 1.30 A. Significantly more hydrogen bonding and hydrophobic interactions were defined between EM1404 and the enzyme than in the substrate ternary complex. The lactone ring of EM1404 accounts for important interactions with the enzyme, whereas the amide group at the opposite end of the inhibitor contributes to the stability of three protein loops involved in the construction of the substrate binding site. EM1404 has a strong competitive inhibition, with a Ki of 6.9+/-1.4 nM, demonstrating 40 times higher affinity than that of the best inhibitor previously reported. This is observed despite the fact that the inhibitor occupies only part of the binding cavity. Attempts to soak the inhibitor into crystals of the binary complex with NADP were unsuccessful, yielding a structure with a polyethylene glycol fragment occupying the substrate binding site. The relative crystal packing is discussed. Combined studies of small molecule inhibitor synthesis, x-ray crystallography, enzyme inhibition, and molecular modeling make it possible to analyze the plasticity of the substrate binding site of the enzyme, which is essential for developing more potent and specific inhibitors for hormone-dependent cancer therapy.
 
  Selected figure(s)  
 
Figure 6.
FIGURE 6. Interaction of the lactone ring with Ser-118 in AKR1C enzymes. A, the sequence alignment of several AKR1C family members. B, Ser-118 interaction with EM1404 in 17 -HSD5. Ser-118 hydroxyl forms a strong hydrogen bond (2.8 Å) with the 2'-carbonyl oxygen in the lactone ring. C, superimposition of human 3 -HSD3 with human 17 -HSD5 in the inhibitor binding site shows the steric hindrance from Phe-118 of 3 -HSD3 prevents the binding of the EM1404.
Figure 7.
FIGURE 7. Location of the sub-sites a and b in the binding site in 17 -HSD5·AKR1C3. A, superimposition of different ligands in nine 17 -HSD5·AKR1C3 crystal structures (PDB code: 1S1R, 1S2A, 1S2C, 1RY0, 1RY8, 2FGB, 1Xf0, and 1AFS) using 17 -HSD5·EM1404·NADP (PDB code: 1ZQ5) as a reference on the triose-phosphate isomerase barrel motif. Using EM1404 as reference (colored in cyan), the top view of EM1404 showed two sites (a and b) as having high ligand occupancies (shaded areas), where site a corresponds to the lactone ring in EM1404 and site b is at the location of the acetate ion; B, view of the two sites perpendicular to A. C, location of the binding sites a and b relative to EM1404 in the 17 -HSD5·EM1404·NADP structure. NADP molecule is also shown near EM1404.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 8368-8379) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
18821018 W.L.Miller (2009).
Androgen synthesis in adrenarche.
  Rev Endocr Metab Disord, 10, 3.  
17950253 M.C.Byrns, S.Steckelbroeck, and T.M.Penning (2008).
An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies.
  Biochem Pharmacol, 75, 484-493.  
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.