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PDBsum entry 1s1p

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protein ligands links
Oxidoreductase PDB id
1s1p
Jmol
Contents
Protein chain
315 a.a. *
Ligands
ACT
NAP
MPD
Waters ×432
* Residue conservation analysis
PDB id:
1s1p
Name: Oxidoreductase
Title: Crystal structures of prostaglandin d2 11-ketoreductase (akr1c3) in complex with the non-steroidal anti- inflammatory drugs flufenamic acid and indomethacin
Structure: Aldo-keto reductase family 1 member c3. Chain: a. Synonym: akr1c3, prostaglandin d2 11-ketoreductase, prostaglandin f synthase, 3-alpha-hsd-type-2, 17-beta-hsd- type-5. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.20Å     R-factor:   0.147     R-free:   0.156
Authors: A.L.Lovering,J.P.Ride,C.M.Bunce,J.C.Desmond,S.M.Cummings, S.A.White
Key ref: A.L.Lovering et al. (2004). Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res, 64, 1802-1810. PubMed id: 14996743 DOI: 10.1158/0008-5472.CAN-03-2847
Date:
07-Jan-04     Release date:   23-Mar-04    
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.
315 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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
Bound ligand (Het Group name = MPD)
matches with 63.00% similarity
+
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
Bound ligand (Het Group name = MPD)
matches with 60.00% similarity
+
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: 10.1158/0008-5472.CAN-03-2847 Cancer Res 64:1802-1810 (2004)
PubMed id: 14996743  
 
 
Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin.
A.L.Lovering, J.P.Ride, C.M.Bunce, J.C.Desmond, S.M.Cummings, S.A.White.
 
  ABSTRACT  
 
It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19997560 F.L.Khanim, R.E.Hayden, J.Birtwistle, A.Lodi, S.Tiziani, N.J.Davies, J.P.Ride, M.R.Viant, U.L.Gunther, J.C.Mountford, H.Schrewe, R.M.Green, J.A.Murray, M.T.Drayson, and C.M.Bunce (2009).
Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia.
  PLoS One, 4, e8147.  
19010312 M.C.Byrns, and T.M.Penning (2009).
Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs.
  Chem Biol Interact, 178, 221-227.  
20003443 P.Veliça, N.J.Davies, P.P.Rocha, H.Schrewe, J.P.Ride, and C.M.Bunce (2009).
Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers.
  Mol Cancer, 8, 121.  
19218247 Y.Jin, L.Duan, S.H.Lee, H.J.Kloosterboer, I.A.Blair, and T.M.Penning (2009).
Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism.
  J Biol Chem, 284, 10013-10022.  
18576452 C.Ludwig, P.J.Michiels, A.Lodi, J.Ride, C.Bunce, and U.L.Günther (2008).
Evaluation of solvent accessibility epitopes for different dehydrogenase inhibitors.
  ChemMedChem, 3, 1371-1376.  
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.  
18528521 M.J.Campbell, C.Carlberg, and H.P.Koeffler (2008).
A Role for the PPARgamma in Cancer Therapy.
  PPAR Res, 2008, 314974.  
19000823 Y.H.Wu, T.P.Ko, R.T.Guo, S.M.Hu, L.M.Chuang, and A.H.Wang (2008).
Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2.
  Structure, 16, 1714-1723.
PDB codes: 2zb3 2zb4 2zb7 2zb8
17009925 U.Oppermann (2007).
Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology.
  Annu Rev Pharmacol Toxicol, 47, 293-322.  
16547389 T.Matsunaga, S.Shintani, and A.Hara (2006).
Multiplicity of mammalian reductases for xenobiotic carbonyl compounds.
  Drug Metab Pharmacokinet, 21, 1.  
15929998 J.F.Couture, K.P.de Jésus-Tran, A.M.Roy, L.Cantin, P.L.Côté, P.Legrand, V.Luu-The, F.Labrie, and R.Breton (2005).
Comparison of crystal structures of human type 3 3alpha-hydroxysteroid dehydrogenase reveals an "induced-fit" mechanism and a conserved basic motif involved in the binding of androgen.
  Protein Sci, 14, 1485-1497.
PDB code: 1xjb
  16511129 O.El-Kabbani, S.Ishikura, A.Wagner, C.Schulze-Briese, and A.Hara (2005).
Crystallization and preliminary X-ray diffraction analysis of mouse 3(17)alpha-hydroxysteroid dehydrogenase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 688-690.  
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.