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PDBsum entry 1q5e
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Oxidoreductase PDB id
1q5e

 

 

 

 

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Contents
Protein chain
404 a.a. *
Ligands
HEM
Waters ×89
* Residue conservation analysis
PDB id:
1q5e
Name: Oxidoreductase
Title: Substrate-free cytochrome p450epok
Structure: P450 epoxidase. Chain: a. Synonym: epok, cytochrome p450epok. Engineered: yes
Source: Sorangium cellulosum. Organism_taxid: 56. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.65Å     R-factor:   0.240     R-free:   0.299
Authors: S.Nagano,H.Li,H.Shimizu,C.Nishida,H.Ogura,P.R.Ortiz De Montellano, T.L.Poulos
Key ref:
S.Nagano et al. (2003). Crystal structures of epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P450epoK. J Biol Chem, 278, 44886-44893. PubMed id: 12933799 DOI: 10.1074/jbc.M308115200
Date:
06-Aug-03     Release date:   28-Oct-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9KIZ4  (C167_SORCE) -  Epothilone C/D epoxidase from Sorangium cellulosum
Seq:
Struc: 		419 a.a.
404 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.14.15.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1074/jbc.M308115200 J Biol Chem 278:44886-44893 (2003)
PubMed id: 12933799  
 
 
Crystal structures of epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P450epoK.
S.Nagano, H.Li, H.Shimizu, C.Nishida, H.Ogura, P.R.Ortiz de Montellano, T.L.Poulos.
 
  ABSTRACT  
 
Epothilones are potential anticancer drugs that stabilize microtubules by binding to tubulin in a manner similar to paclitaxel. Cytochrome P450epoK (P450epoK), a heme containing monooxygenase involved in epothilone biosynthesis in the myxobacterium Sorangium cellulosum, catalyzes the epoxidation of epothilones C and D into epothilones A and B, respectively. The 2.10-, 1.93-, and 2.65-A crystal structures reported here for the epothilone D-bound, epothilone B-bound, and substrate-free forms, respectively, are the first crystal structures of an epothilone-binding protein. Although the substrate for P450epoK is the largest of a P450 whose x-ray structure is known, the structural changes along with substrate binding or product release are very minor and the overall fold is similar to other P450s. The epothilones are positioned with the macrolide ring roughly perpendicular to the heme plane and I helix, and the thiazole moiety provides key interactions that very likely are critical in determining substrate specificity. Interestingly, there are strong parallels between the epothilone/P450epoK and paclitaxel/tubulin interactions. Based on structural similarities, a plausible epothilone tubulin-binding mode is proposed.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Tubulin-binding anti-cancer drugs. a, structure of epothilones and epoxidation reaction catalyzed by P450epoK. Epothilones D and B have higher tubulin polymerization activity and cytotoxicity than epothilones C and A, respectively (8, 45). b, paclitaxel. Taxane skeleton is composed of rings A-D. c, eleutherobin; d, sarcodictyin; e, discodemolide. 		Figure 7.
FIG. 7. Stereo view showing substrate-binding site. Atom colors are the same as in Fig. 4. H-bonds, which bridge between epothilone and protein atoms, are shown as broken yellow lines. a, epothilone D-bound form; b, epothilone B-bound form.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 44886-44893) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20121095 C.T.Walsh, and M.A.Fischbach (2010).
Natural products version 2.0: connecting genes to molecules.
  J Am Chem Soc, 132, 2469-2493.  
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.  
20797613 P.M.Kells, H.Ouellet, J.Santos-Aberturas, J.F.Aparicio, and L.M.Podust (2010).
Structure of cytochrome P450 PimD suggests epoxidation of the polyene macrolide pimaricin occurs via a hydroperoxoferric intermediate.
  Chem Biol, 17, 841-851.
PDB codes: 2x9p 2xbk
20446763 T.C.Pochapsky, S.Kazanis, and M.Dang (2010).
Conformational plasticity and structure/function relationships in cytochromes P450.
  Antioxid Redox Signal, 13, 1273-1296.  
19179341 A.Nayeem, S.J.Chiang, S.W.Liu, Y.Sun, L.You, and J.Basch (2009).
Engineering enzymes for improved catalytic efficiency: a computational study of site mutagenesis in epothilone-B hydroxylase.
  Protein Eng Des Sel, 22, 257-266.  
19153781 D.Rusinska-Roszak, and M.Lozynski (2009).
De(side chain) model of epothilone: bioconformer interconversions DFT study.
  J Mol Model, 15, 859-869.  
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
19265398 S.Balaz (2009).
Modeling kinetics of subcellular disposition of chemicals.
  Chem Rev, 109, 1793-1899.  
18513977 B.OuYang, S.S.Pochapsky, M.Dang, and T.C.Pochapsky (2008).
A functional proline switch in cytochrome P450cam.
  Structure, 16, 916-923.  
17534532 A.W.Munro, H.M.Girvan, and K.J.McLean (2007).
Variations on a (t)heme--novel mechanisms, redox partners and catalytic functions in the cytochrome P450 superfamily.
  Nat Prod Rep, 24, 585-609.  
17390000 K.H.Altmann, and J.Gertsch (2007).
Anticancer drugs from nature--natural products as a unique source of new microtubule-stabilizing agents.
  Nat Prod Rep, 24, 327-357.  
16825192 D.H.Sherman, S.Li, L.V.Yermalitskaya, Y.Kim, J.A.Smith, M.R.Waterman, and L.M.Podust (2006).
The structural basis for substrate anchoring, active site selectivity, and product formation by P450 PikC from Streptomyces venezuelae.
  J Biol Chem, 281, 26289-26297.
PDB codes: 2bvj 2c6h 2c7x 2cd8
16793528 M.J.de Groot (2006).
Designing better drugs: predicting cytochrome P450 metabolism.
  Drug Discov Today, 11, 601-606.  
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.

 

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