PDBsum entry 1h5z

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Oxidoreductase PDB id
Protein chain
435 a.a. *
Waters ×280
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Cytochrome p450 14 alpha-sterol demethylase (cyp51) from mycobacterium tuberculosis in ferric low-spin state
Structure: Cytochrome p450 51. Chain: a. Synonym: cyp51, sterol 14-alpha demethylase, lanosterol 14-alpha demethylase, p450-14dm. Engineered: yes. Other_details: cys 394 binds heme iron
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Strain: hms174. Cellular_location: cytoplasm. Plasmid: pet17b. Gene: cyp51 or rv0764c or mtcy369.09c. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.05Å     R-factor:   0.185     R-free:   0.236
Authors: L.M.Podust,M.Arase,M.R.Waterman
Key ref:
L.M.Podust et al. (2004). Estriol bound and ligand-free structures of sterol 14alpha-demethylase. Structure, 12, 1937-1945. PubMed id: 15530358 DOI: 10.1016/j.str.2004.08.009
31-May-01     Release date:   03-Oct-03    
Go to PROCHECK summary

Protein chain
P9WPP9  (CP51_MYCTU) -  Lanosterol 14-alpha demethylase
451 a.a.
435 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Sterol 14-alpha-demethylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Sterol ring B, C, D modification
      Reaction: A 14-alpha-methylsteroid + 3 O2 + 3 NADPH = a Delta14-steroid + formate + 3 NADP+ + 4 H2O
+ 3 × O(2)
+ 3 × NADPH
= Delta(14)-steroid
Bound ligand (Het Group name = HEM)
matches with 62.00% similarity
+ formate
+ 3 × NADP(+)
+ 4 × H(2)O
      Cofactor: Heme-thiolate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     demethylation   6 terms 
  Biochemical function     oxidoreductase activity     7 terms  


DOI no: 10.1016/j.str.2004.08.009 Structure 12:1937-1945 (2004)
PubMed id: 15530358  
Estriol bound and ligand-free structures of sterol 14alpha-demethylase.
L.M.Podust, L.V.Yermalitskaya, G.I.Lepesheva, V.N.Podust, E.A.Dalmasso, M.R.Waterman.
Sterol 14alpha-demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes and drug targets in antifungal therapy. Here, we report CYP51 structures in ligand-free and estriol bound forms. Using estriol as a probe, we determined orientation of the substrate in the active site, elucidated protein contacts with the invariant 3beta-hydroxy group of a sterol, and identified F78 as a key discriminator between 4alpha-methylated and 4alpha,beta-dimethylated substrates. Analysis of CYP51 dynamics revealed that the C helix undergoes helix-coil transition upon binding and dissociation of a ligand. Loss of helical structure of the C helix in the ligand-free form results in an unprecedented opening of the substrate binding site. Upon binding of estriol, the BC loop loses contacts with molecular surface and tends to adopt a closed conformation. A mechanism for azole resistance in the yeast pathogen Candida albicans associated with mutations in the ERG11 gene encoding CYP51 is suggested based on CYP51 protein dynamics.
  Selected figure(s)  
Figure 6.
Figure 6. Estriol Binding in the Active Site of MTCYP51(A) Stereo view of estriol bound in the active site of MTCYP51.(B) Electron density for estriol represented by a fragment of the 2F[o]-F[c] composite omit map contoured at 1.2s.(C) Estriol and F78 are represented by their van der Waals radii in the binding site of MTCYP51, in the same orientations as in stereo view (A).
  The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 1937-1945) copyright 2004.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21370476 R.Guillon, F.Pagniez, F.Giraud, D.Crépin, C.Picot, M.Le Borgne, F.Morio, M.Duflos, C.Logé, and P.Le Pape (2011).
Design, synthesis, and in vitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols.
  ChemMedChem, 6, 816-825.  
19593597 C.Sheng, S.Chen, H.Ji, G.Dong, X.Che, W.Wang, Z.Miao, J.Yao, J.Lü, W.Guo, and W.Zhang (2010).
Evolutionary trace analysis of CYP51 family: implication for site-directed mutagenesis and novel antifungal drug design.
  J Mol Model, 16, 279-284.  
19923211 G.I.Lepesheva, H.W.Park, T.Y.Hargrove, B.Vanhollebeke, Z.Wawrzak, J.M.Harp, M.Sundaramoorthy, W.D.Nes, E.Pays, M.Chaudhuri, F.Villalta, and M.R.Waterman (2010).
Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections.
  J Biol Chem, 285, 1773-1780.
PDB codes: 3g1q 3gw9
20305029 H.J.Cools, J.E.Parker, D.E.Kelly, J.A.Lucas, B.A.Fraaije, and S.L.Kelly (2010).
Heterologous expression of mutated eburicol 14alpha-demethylase (CYP51) proteins of Mycosphaerella graminicola to assess effects on azole fungicide sensitivity and intrinsic protein function.
  Appl Environ Microbiol, 76, 2866-2872.  
19635450 H.Ouellet, J.B.Johnston, and P.R.Ortiz de Montellano (2010).
The Mycobacterium tuberculosis cytochrome P450 system.
  Arch Biochem Biophys, 493, 82-95.  
20669042 L.E.Thornton, S.G.Rupasinghe, H.Peng, M.A.Schuler, and M.M.Neff (2010).
Arabidopsis CYP72C1 is an atypical cytochrome P450 that inactivates brassinosteroids.
  Plant Mol Biol, 74, 167-181.  
20297780 Y.T.Lee, R.F.Wilson, I.Rupniewski, and D.B.Goodin (2010).
P450cam visits an open conformation in the absence of substrate.
  Biochemistry, 49, 3412-3419.
PDB codes: 3l61 3l62 3l63
19190730 C.K.Chen, P.S.Doyle, L.V.Yermalitskaya, Z.B.Mackey, K.K.Ang, J.H.McKerrow, and L.M.Podust (2009).
Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit.
  PLoS Negl Trop Dis, 3, e372.
PDB codes: 2w09 2w0a 2w0b
19470512 C.Sheng, Z.Miao, H.Ji, J.Yao, W.Wang, X.Che, G.Dong, J.Lü, W.Guo, and W.Zhang (2009).
Three-dimensional model of lanosterol 14 alpha-demethylase from Cryptococcus neoformans: active-site characterization and insights into azole binding.
  Antimicrob Agents Chemother, 53, 3487-3495.  
19418481 G.P.Cañas-Gutiérrez, M.J.Angarita-Velásquez, J.M.Restrepo-Flórez, P.Rodríguez, C.X.Moreno, and R.Arango (2009).
Analysis of the CYP51 gene and encoded protein in propiconazole-resistant isolates of Mycosphaerella fijiensis.
  Pest Manag Sci, 65, 892-899.  
19074393 L.H.Xu, S.Fushinobu, H.Ikeda, T.Wakagi, and H.Shoun (2009).
Crystal structures of cytochrome P450 105P1 from Streptomyces avermitilis: conformational flexibility and histidine ligation state.
  J Bacteriol, 191, 1211-1219.
PDB codes: 3e5j 3e5k 3e5l
18367444 A.N.Eddine, J.P.von Kries, M.V.Podust, T.Warrier, S.H.Kaufmann, and L.M.Podust (2008).
X-ray structure of 4,4'-dihydroxybenzophenone mimicking sterol substrate in the active site of sterol 14alpha-demethylase (CYP51).
  J Biol Chem, 283, 15152-15159.
PDB code: 2vku
18818197 K.J.McLean, P.Carroll, D.G.Lewis, A.J.Dunford, H.E.Seward, R.Neeli, M.R.Cheesman, L.Marsollier, P.Douglas, W.E.Smith, I.Rosenkrands, S.T.Cole, D.Leys, T.Parish, and A.W.Munro (2008).
  J Biol Chem, 283, 33406-33416.
PDB code: 3cxv
19179758 M.S.Achary, and H.A.Nagarajam (2008).
Comparative docking studies of CYP1b1 and its PCG-associated mutant forms.
  J Biosci, 33, 699-713.  
17553785 A.J.Dunford, K.J.McLean, M.Sabri, H.E.Seward, D.J.Heyes, N.S.Scrutton, and A.W.Munro (2007).
Rapid P450 heme iron reduction by laser photoexcitation of Mycobacterium tuberculosis CYP121 and CYP51B1. Analysis of CO complexation reactions and reversibility of the P450/P420 equilibrium.
  J Biol Chem, 282, 24816-24824.  
17585868 G.I.Lepesheva, M.Seliskar, C.G.Knutson, N.V.Stourman, D.Rozman, and M.R.Waterman (2007).
Conformational dynamics in the F/G segment of CYP51 from Mycobacterium tuberculosis monitored by FRET.
  Arch Biochem Biophys, 464, 221-227.  
17846131 L.M.Podust, J.P.von Kries, A.N.Eddine, Y.Kim, L.V.Yermalitskaya, R.Kuehne, H.Ouellet, T.Warrier, M.Alteköster, J.S.Lee, J.Rademann, H.Oschkinat, S.H.Kaufmann, and M.R.Waterman (2007).
Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography.
  Antimicrob Agents Chemother, 51, 3915-3923.
PDB codes: 2bz9 2ci0 2cib
18005930 S.G.Rupasinghe, H.Duan, H.L.Frericks Schmidt, D.A.Berthold, C.M.Rienstra, and M.A.Schuler (2007).
High-yield expression and purification of isotopically labeled cytochrome P450 monooxygenases for solid-state NMR spectroscopy.
  Biochim Biophys Acta, 1768, 3061-3070.  
17897373 S.Znaidi, X.De Deken, S.Weber, T.Rigby, A.Nantel, and M.Raymond (2007).
The zinc cluster transcription factor Tac1p regulates PDR16 expression in Candida albicans.
  Mol Microbiol, 66, 440-452.  
16321980 G.I.Lepesheva, N.G.Zaitseva, W.D.Nes, W.Zhou, M.Arase, J.Liu, G.C.Hill, and M.R.Waterman (2006).
CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B' helix defines substrate preferences of sterol 14alpha-demethylase.
  J Biol Chem, 281, 3577-3585.  
16872679 I.A.Pikuleva (2006).
Cytochrome P450s and cholesterol homeostasis.
  Pharmacol Ther, 112, 761-773.  
16581251 K.J.McLean, D.Clift, D.G.Lewis, M.Sabri, P.R.Balding, M.J.Sutcliffe, D.Leys, and A.W.Munro (2006).
The preponderance of P450s in the Mycobacterium tuberculosis genome.
  Trends Microbiol, 14, 220-228.  
16028060 J.Bojunga, C.Welsch, I.Antes, M.Albrecht, T.Lengauer, and S.Zeuzem (2005).
Structural and functional analysis of a novel mutation of CYP21B in a heterozygote carrier of 21-hydroxylase deficiency.
  Hum Genet, 117, 558-564.  
16028306 K.Schleinkofer, Sudarko, P.J.Winn, S.K.Lüdemann, and R.C.Wade (2005).
Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling?
  EMBO Rep, 6, 584-589.  
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.