PDBsum entry 1mrq

Go to PDB code: 
protein ligands links
Oxidoreductase PDB id
Protein chain
323 a.a. *
Waters ×321
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of human 20alpha-hsd in ternary complex wi and 20alpha-hydroxy-progesterone
Structure: Aldo-keto reductase family 1 member c1. Chain: a. Synonym: 20alpha-hydroxysteroid dehydrogenase, trans-1,2- dihydrobenzene-1,2-diol dehydrogenase, high-affinity hepati acid-binding protein, hbab, chlordecone reductase homolog h dihydrodiol dehydrogenase 2, dd2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: liver. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
1.59Å     R-factor:   0.173     R-free:   0.194
Authors: J.F.Couture,P.Legrand,L.Cantin,V.Luu-The,F.Labrie,R.Breton
Key ref:
J.F.Couture et al. (2003). Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids. J Mol Biol, 331, 593-604. PubMed id: 12899831 DOI: 10.1016/S0022-2836(03)00762-9
18-Sep-02     Release date:   30-Sep-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q04828  (AK1C1_HUMAN) -  Aldo-keto reductase family 1 member C1
323 a.a.
323 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.  - Indanol dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Indan-1-ol + NAD(P)(+) = indanone + NAD(P)H
Bound ligand (Het Group name = STR)
matches with 43.48% similarity
Bound ligand (Het Group name = NAP)
corresponds exactly
= indanone
   Enzyme class 2: E.C.  - 20-alpha-hydroxysteroid dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 17-alpha,20-alpha-dihydroxypregn-4-en-3-one + NAD(P)(+) = 17-alpha- hydroxyprogesterone + NAD(P)H
Bound ligand (Het Group name = STR)
matches with 95.83% similarity
Bound ligand (Het Group name = NAP)
corresponds exactly
= 17-alpha- hydroxyprogesterone
   Enzyme class 3: E.C.  - Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Trans-1,2-dihydrobenzene-1,2-diol + NADP+ = catechol + NADPH
Bound ligand (Het Group name = NAP)
corresponds exactly
= catechol
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     cytoplasm   2 terms 
  Biological process     daunorubicin metabolic process   17 terms 
  Biochemical function     oxidoreductase activity     12 terms  


DOI no: 10.1016/S0022-2836(03)00762-9 J Mol Biol 331:593-604 (2003)
PubMed id: 12899831  
Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and site-directed mutagenesis studies lead to the identification of an alternative binding site for C21-steroids.
J.F.Couture, P.Legrand, L.Cantin, V.Luu-The, F.Labrie, R.Breton.
Human 20alpha-hydroxysteroid dehydrogenase (h20alpha-HSD; AKR1C1) catalyzes the transformation of progesterone (Prog) into 20alpha-hydroxy-progesterone (20alpha-OHProg). Although h20alpha-HSD shares 98% sequence identity with human type 3 3alpha-HSD (h3alpha-HSD3, AKR1C2), these two enzymes differ greatly in their activities. In order to explain these differences, we have solved the crystal structure of h20alpha-HSD in a ternary complex with NADP(+) and 20alpha-OHProg at 1.59A resolution. The steroid is stabilized by numerous hydrophobic interactions and a hydrogen bond between its O20 and the N(epsilon ) atom of His222. This new interaction prevents the formation of a hydrogen bond with the cofactor, as seen in h3alpha-HSD3 ternary complexes. By combining structural, direct mutagenesis and kinetic studies, we found that the H(222)I substitution decreases the K(m) value for the cofactor 95-fold. With these results, we hypothesize that the rotation of the lateral chain of His222 could be a mediating step between the transformation of Prog and the release of the cofactor. Moreover, crystal structure analysis and direct mutagenesis experiments lead us to identify a new residue involved in the binding of Prog. Indeed, the R(304)L substitution leads to a 65-fold decrease in the K(m) value for Prog reduction. We thus propose that Prog is maintained in a new steroid-binding site composed mainly of residues found in the carboxy-terminal region of the protein.
  Selected figure(s)  
Figure 1.
Figure 1. Schematic representation of Prog. (A) The carbon atoms of the steroid are numbered and the cycles designated by letters. (B) Stereospecific transformation of Prog into 20a-hydroxy-progesterone. Faces of steroids are labeled a and b.
Figure 3.
Figure 3. Stereo view of the superposition of a h20a-HSD complex with human type 3 h3a-HSD complexes. 20a-HSD and its ligands are in grey; type 3 h3a-HSD, NADP+ and testosterone (RCSB PDB entry, 1J96) and human type 3 h3a-HSD in complex with ursodeoxycholate (RCSB PDB entry, 1IHI) are depicted in orange and black, respectively. Phosphate atoms are depicted in pink, oxygen atoms in red and nitrogen atoms in blue (created with MOLSCRIPT).[47]
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 331, 593-604) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21217827 J.W.Arthur, and J.K.Reichardt (2010).
Modeling single nucleotide polymorphisms in the human AKR1C1 and AKR1C2 genes: implications for functional and genotyping analyses.
  PLoS One, 5, e15604.  
19237748 U.Dhagat, S.Endo, H.Mamiya, A.Hara, and O.El-Kabbani (2009).
Structure of the G225P/G226P mutant of mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) ternary complex: implications for the binding of inhibitor and substrate.
  Acta Crystallogr D Biol Crystallogr, 65, 257-265.
PDB code: 3cv6
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.  
18300247 J.G.Olsen, L.Pedersen, C.L.Christensen, O.Olsen, and A.Henriksen (2008).
Barley aldose reductase: structure, cofactor binding, and substrate recognition in the aldo/keto reductase 4C family.
  Proteins, 71, 1572-1581.
PDB codes: 2bgq 2bgs 2vdg
18407998 L.Di Costanzo, J.E.Drury, T.M.Penning, and D.W.Christianson (2008).
Crystal structure of human liver Delta4-3-ketosteroid 5beta-reductase (AKR1D1) and implications for substrate binding and catalysis.
  J Biol Chem, 283, 16830-16839.
PDB codes: 3bur 3buv 3bv7 3cmf 3cot
18060684 T.M.Penning, Y.Jin, T.L.Rizner, and D.R.Bauman (2008).
Pre-receptor regulation of the androgen receptor.
  Mol Cell Endocrinol, 281, 1-8.  
17560657 A.M.Hosie, M.E.Wilkins, and T.G.Smart (2007).
Neurosteroid binding sites on GABA(A) receptors.
  Pharmacol Ther, 116, 7.  
  17909281 U.Dhagat, V.Carbone, R.P.Chung, C.Schulze-Briese, S.Endo, A.Hara, and O.El-Kabbani (2007).
Structure of 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) holoenzyme from an orthorhombic crystal form: an insight into the bifunctionality of the enzyme.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 825-830.
PDB code: 2p5n
16645592 L.A.Gildea, C.A.Ryan, L.M.Foertsch, J.M.Kennedy, R.J.Dearman, I.Kimber, and G.F.Gerberick (2006).
Identification of gene expression changes induced by chemical allergens in dendritic cells: opportunities for skin sensitization testing.
  J Invest Dermatol, 126, 1813-1822.  
16547389 T.Matsunaga, S.Shintani, and A.Hara (2006).
Multiplicity of mammalian reductases for xenobiotic carbonyl compounds.
  Drug Metab Pharmacokinet, 21, 1.  
17059222 Y.Jin, and T.M.Penning (2006).
Multiple steps determine the overall rate of the reduction of 5alpha-dihydrotestosterone catalyzed by human type 3 3alpha-hydroxysteroid dehydrogenase: implications for the elimination of androgens.
  Biochemistry, 45, 13054-13063.  
15929998 J.F.Couture, 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.  
15577209 S.Ishikura, N.Usami, S.Nakajima, A.Kameyama, H.Shiraishi, V.Carbone, O.El-Kabbani, and A.Hara (2004).
Characterization of two isoforms of mouse 3(17)alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase family.
  Biol Pharm Bull, 27, 1939-1945.  
14672942 S.Steckelbroeck, Y.Jin, S.Gopishetty, B.Oyesanmi, and T.M.Penning (2004).
Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action.
  J Biol Chem, 279, 10784-10795.  
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.