 |
PDBsum entry 1n6b
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
1n6b
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Oxidoreductase
|
|
|
Title:
|
|
Microsomal cytochrome p450 2c5/3lvdh complex with a dimethyl derivative of sulfaphenazole
|
|
Structure:
|
|
Cytochrome p450 2c5. Chain: a. Synonym: cypiic5, p450 1, progesterone 21-hydroxylase, p450iic5. Engineered: yes
|
|
Source:
|
|
Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Organ: liver. Gene: cyp2c5. Expressed in: escherichia coli. Expression_system_taxid: 562.
|
|
Resolution:
|
|
|
2.30Å
|
R-factor:
|
0.257
|
R-free:
|
0.292
|
|
|
Authors:
|
|
M.R.Wester,E.F.Johnson,C.Marques-Soares,P.M.Dansette,D.Mansuy, C.D.Stout
|
Key ref:
|
|
M.R.Wester
et al.
(2003).
Structure of a substrate complex of mammalian cytochrome P450 2C5 at 2.3 A resolution: evidence for multiple substrate binding modes.
Biochemistry,
42,
6370-6379.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
09-Nov-02
|
Release date:
|
03-Jun-03
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P00179
(CP2C5_RABIT) -
Cytochrome P450 2C5 from Oryctolagus cuniculus
|
|
|
|
Seq:
Struc:
|
|
|
|
487 a.a.
462 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
*
PDB and UniProt seqs differ
at 5 residue positions (black
crosses)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.1.14.14.1
- unspecific monooxygenase.
|
|
|
|
|
|
|
Reaction:
|
|
an organic molecule + reduced [NADPH--hemoprotein reductase] + O2 = an alcohol + oxidized [NADPH--hemoprotein reductase] + H2O + H+
|
|
|
|
|
|
organic molecule
|
+
|
reduced [NADPH--hemoprotein reductase]
|
+
|
O2
|
=
|
alcohol
|
+
|
oxidized [NADPH--hemoprotein reductase]
|
+
|
H2O
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
Cofactor:
|
|
Heme-thiolate
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Biochemistry
42:6370-6379
(2003)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Structure of a substrate complex of mammalian cytochrome P450 2C5 at 2.3 A resolution: evidence for multiple substrate binding modes.
|
|
M.R.Wester,
E.F.Johnson,
C.Marques-Soares,
P.M.Dansette,
D.Mansuy,
C.D.Stout.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The structure of rabbit microsomal cytochrome P450 2C5/3LVdH complexed with a
substrate, 4-methyl-N-methyl-N-(2-phenyl-2H-pyrazol-3-yl)benzenesulfonamide
(DMZ), was determined by X-ray crystallography to 2.3 A resolution. Substrate
docking studies and electron density maps indicate that DMZ binds to the enzyme
in two antiparallel orientations of the long axis of the substrate. One
orientation places the principal site of hydroxylation, the 4-methyl group, 4.4
A from the heme Fe, whereas the alternate conformation positions the second,
infrequent site of hydroxylation at >5.9 A from the heme Fe. Comparison of
this structure to that obtained previously for the enzyme indicates that the
protein closes around the substrate and prevents open access of water from bulk
solvent to the heme Fe. This reflects a approximately 1.5 A movement of the F
and G helices relative to helix I. The present structure provides a complete
model for the protein from residues 27-488 and defines two new helices F' and
G'. The G' helix is likely to contribute to interactions of the enzyme with
membranes. The relatively large active site, as compared to the volume occupied
by the substrate, and the flexibility of the enzyme are likely to underlie the
capacity of drug-metabolizing enzymes to metabolize structurally diverse
substrates of different sizes.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
M.Ma,
S.G.Bell,
W.Yang,
Y.Hao,
N.H.Rees,
M.Bartlam,
W.Zhou,
L.L.Wong,
and
Z.Rao
(2011).
Structural Analysis of CYP101C1 from Novosphingobium aromaticivorans DSM12444.
|
| |
Chembiochem,
12,
88-99.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
H.Sun,
and
D.O.Scott
(2010).
Structure-based drug metabolism predictions for drug design.
|
| |
Chem Biol Drug Des,
75,
3.
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
N.Krishnamoorthy,
P.Gajendrarao,
S.Thangapandian,
Y.Lee,
and
K.W.Lee
(2010).
Probing possible egress channels for multiple ligands in human CYP3A4: a molecular modeling study.
|
| |
J Mol Model,
16,
607-614.
|
|
|
|
|
|
|
R.J.Unwalla,
J.B.Cross,
S.Salaniwal,
A.D.Shilling,
L.Leung,
J.Kao,
and
C.Humblet
(2010).
Using a homology model of cytochrome P450 2D6 to predict substrate site of metabolism.
|
| |
J Comput Aided Mol Des,
24,
237-256.
|
|
|
|
|
|
|
T.C.Pochapsky,
S.Kazanis,
and
M.Dang
(2010).
Conformational plasticity and structure/function relationships in cytochromes P450.
|
| |
Antioxid Redox Signal,
13,
1273-1296.
|
|
|
|
|
|
|
I.G.Denisov,
D.J.Frank,
and
S.G.Sligar
(2009).
Cooperative properties of cytochromes P450.
|
| |
Pharmacol Ther,
124,
151-167.
|
|
|
|
|
|
|
M.K.Leong,
Y.M.Chen,
H.B.Chen,
and
P.H.Chen
(2009).
Development of a New Predictive Model for Interactions with Human Cytochrome P450 2A6 Using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) Approach.
|
| |
Pharm Res,
26,
987.
|
|
|
|
|
|
|
S.C.Gay,
L.Sun,
K.Maekawa,
J.R.Halpert,
and
C.D.Stout
(2009).
Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand-induced structural response through alpha-helical repositioning.
|
| |
Biochemistry,
48,
4762-4771.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.Dubey,
S.Idicula-Thomas,
M.Anwaruddin,
C.Saravanan,
R.R.Varma,
and
A.Maitra
(2009).
A novel 9-bp insertion detected in steroid 21-hydroxylase gene (CYP21A2): prediction of its structural and functional implications by computational methods.
|
| |
J Biomed Sci,
16,
3.
|
|
|
|
|
|
|
E.M.Isin,
and
F.P.Guengerich
(2008).
Substrate binding to cytochromes P450.
|
| |
Anal Bioanal Chem,
392,
1019-1030.
|
|
|
|
|
|
|
G.Niu,
Z.Wen,
S.G.Rupasinghe,
R.S.Zeng,
M.R.Berenbaum,
and
M.A.Schuler
(2008).
Aflatoxin B1 detoxification by CYP321A1 in Helicoverpa zea.
|
| |
Arch Insect Biochem Physiol,
69,
32-45.
|
|
|
|
|
|
|
J.D'Agostino,
X.Zhang,
H.Wu,
G.Ling,
S.Wang,
Q.Y.Zhang,
F.Liu,
and
X.Ding
(2008).
Characterization of CYP2A13*2, a variant cytochrome P450 allele previously found to be associated with decreased incidences of lung adenocarcinoma in smokers.
|
| |
Drug Metab Dispos,
36,
2316-2323.
|
|
|
|
|
|
|
J.D.Maréchal,
C.A.Kemp,
G.C.Roberts,
M.J.Paine,
C.R.Wolf,
and
M.J.Sutcliffe
(2008).
Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions.
|
| |
Br J Pharmacol,
153,
S82-S89.
|
|
|
|
|
|
|
R.K.Hughes,
F.K.Yousafzai,
R.Ashton,
I.R.Chechetkin,
S.A.Fairhurst,
M.Hamberg,
and
R.Casey
(2008).
Evidence for communality in the primary determinants of CYP74 catalysis and of structural similarities between CYP74 and classical mammalian P450 enzymes.
|
| |
Proteins,
72,
1199-1211.
|
|
|
|
|
|
|
U.M.Kent,
C.Sridar,
G.Spahlinger,
and
P.F.Hollenberg
(2008).
Modification of serine 360 by a reactive intermediate of 17-alpha-ethynylestradiol results in mechanism-based inactivation of cytochrome P450s 2B1 and 2B6.
|
| |
Chem Res Toxicol,
21,
1956-1963.
|
|
|
|
|
|
|
W.Li,
Y.Tang,
H.Liu,
J.Cheng,
W.Zhu,
and
H.Jiang
(2008).
Probing ligand binding modes of human cytochrome P450 2J2 by homology modeling, molecular dynamics simulation, and flexible molecular docking.
|
| |
Proteins,
71,
938-949.
|
|
|
|
|
|
|
A.J.Annalora,
E.Bobrovnikov-Marjon,
R.Serda,
A.Pastuszyn,
S.E.Graham,
C.B.Marcus,
and
J.L.Omdahl
(2007).
Hybrid homology modeling and mutational analysis of cytochrome P450C24A1 (CYP24A1) of the Vitamin D pathway: insights into substrate specificity and membrane bound structure-function.
|
| |
Arch Biochem Biophys,
460,
262-273.
|
|
|
|
|
|
|
B.D.Smith,
J.L.Sanders,
P.R.Porubsky,
G.H.Lushington,
C.D.Stout,
and
E.E.Scott
(2007).
Structure of the human lung cytochrome P450 2A13.
|
| |
J Biol Chem,
282,
17306-17313.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
C.de Graaf,
C.Oostenbrink,
P.H.Keizers,
B.M.van Vugt-Lussenburg,
J.N.Commandeur,
and
N.P.Vermeulen
(2007).
Free energies of binding of R- and S-propranolol to wild-type and F483A mutant cytochrome P450 2D6 from molecular dynamics simulations.
|
| |
Eur Biophys J,
36,
589-599.
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
P.Lafite,
F.André,
D.C.Zeldin,
P.M.Dansette,
and
D.Mansuy
(2007).
Unusual regioselectivity and active site topology of human cytochrome P450 2J2.
|
| |
Biochemistry,
46,
10237-10247.
|
|
|
|
|
|
|
R.P.Kommaddi,
C.M.Turman,
B.Moorthy,
L.Wang,
H.W.Strobel,
and
V.Ravindranath
(2007).
An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA-reactive metabolites.
|
| |
J Neurochem,
102,
867-877.
|
|
|
|
|
|
|
S.G.Rupasinghe,
H.Duan,
and
M.A.Schuler
(2007).
Molecular definitions of fatty acid hydroxylases in Arabidopsis thaliana.
|
| |
Proteins,
68,
279-293.
|
|
|
|
|
|
|
W.Mao,
M.A.Schuler,
and
M.R.Berenbaum
(2007).
Cytochrome P450s in Papilio multicaudatus and the transition from oligophagy to polyphagy in the Papilionidae.
|
| |
Insect Mol Biol,
16,
481-490.
|
|
|
|
|
|
|
A.Seifert,
S.Tatzel,
R.D.Schmid,
and
J.Pleiss
(2006).
Multiple molecular dynamics simulations of human p450 monooxygenase CYP2C9: the molecular basis of substrate binding and regioselectivity toward warfarin.
|
| |
Proteins,
64,
147-155.
|
|
|
|
|
|
|
B.K.Muralidhara,
S.Negi,
C.C.Chin,
W.Braun,
and
J.R.Halpert
(2006).
Conformational flexibility of mammalian cytochrome P450 2B4 in binding imidazole inhibitors with different ring chemistry and side chains. Solution thermodynamics and molecular modeling.
|
| |
J Biol Chem,
281,
8051-8061.
|
|
|
|
|
|
|
D.E.Prosser,
Y.Guo,
Z.Jia,
and
G.Jones
(2006).
Structural motif-based homology modeling of CYP27A1 and site-directed mutational analyses affecting vitamin D hydroxylation.
|
| |
Biophys J,
90,
3389-3409.
|
|
|
|
|
|
|
J.T.Pearson,
J.J.Hill,
J.Swank,
N.Isoherranen,
K.L.Kunze,
and
W.M.Atkins
(2006).
Surface plasmon resonance analysis of antifungal azoles binding to CYP3A4 with kinetic resolution of multiple binding orientations.
|
| |
Biochemistry,
45,
6341-6353.
|
|
|
|
|
|
|
K.P.Ravindranathan,
E.Gallicchio,
R.A.Friesner,
A.E.McDermott,
and
R.M.Levy
(2006).
Conformational equilibrium of cytochrome P450 BM-3 complexed with N-palmitoylglycine: a replica exchange molecular dynamics study.
|
| |
J Am Chem Soc,
128,
5786-5791.
|
|
|
|
|
|
|
M.J.de Groot
(2006).
Designing better drugs: predicting cytochrome P450 metabolism.
|
| |
Drug Discov Today,
11,
601-606.
|
|
|
|
|
|
|
W.Mao,
S.Rupasinghe,
A.R.Zangerl,
M.A.Schuler,
and
M.R.Berenbaum
(2006).
Remarkable substrate-specificity of CYP6AB3 in Depressaria pastinacella, a highly specialized caterpillar.
|
| |
Insect Mol Biol,
15,
169-179.
|
|
|
|
|
|
|
Y.Zhao,
M.A.White,
B.K.Muralidhara,
L.Sun,
J.R.Halpert,
and
C.D.Stout
(2006).
Structure of microsomal cytochrome P450 2B4 complexed with the antifungal drug bifonazole: insight into P450 conformational plasticity and membrane interaction.
|
| |
J Biol Chem,
281,
5973-5981.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
A.E.Rettie,
and
J.P.Jones
(2005).
Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics.
|
| |
Annu Rev Pharmacol Toxicol,
45,
477-494.
|
|
|
|
|
|
|
C.Loge,
M.Le Borgne,
P.Marchand,
J.M.Robert,
G.Le Baut,
M.Palzer,
and
R.W.Hartmann
(2005).
Three-dimensional model of cytochrome P450 human aromatase.
|
| |
J Enzyme Inhib Med Chem,
20,
581-585.
|
|
|
|
|
|
|
E.E.Scott,
and
J.R.Halpert
(2005).
Structures of cytochrome P450 3A4.
|
| |
Trends Biochem Sci,
30,
5-7.
|
|
|
|
|
|
|
J.M.Kriegl,
T.Arnhold,
B.Beck,
and
T.Fox
(2005).
A support vector machine approach to classify human cytochrome P450 3A4 inhibitors.
|
| |
J Comput Aided Mol Des,
19,
189-201.
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
N.Krone,
F.G.Riepe,
J.Grötzinger,
C.J.Partsch,
J.Brämswig,
and
W.G.Sippell
(2005).
The residue E351 is essential for the activity of human 21-hydroxylase: evidence from a naturally occurring novel point mutation compared with artificial mutants generated by single amino acid substitutions.
|
| |
J Mol Med,
83,
561-568.
|
|
|
|
|
|
|
S.B.Kirton,
C.W.Murray,
M.L.Verdonk,
and
R.D.Taylor
(2005).
Prediction of binding modes for ligands in the cytochromes P450 and other heme-containing proteins.
|
| |
Proteins,
58,
836-844.
|
|
|
|
|
|
|
S.J.Chinta,
R.P.Kommaddi,
C.M.Turman,
H.W.Strobel,
and
V.Ravindranath
(2005).
Constitutive expression and localization of cytochrome P-450 1A1 in rat and human brain: presence of a splice variant form in human brain.
|
| |
J Neurochem,
93,
724-736.
|
|
|
|
|
|
|
W.M.Atkins
(2005).
Non-Michaelis-Menten kinetics in cytochrome P450-catalyzed reactions.
|
| |
Annu Rev Pharmacol Toxicol,
45,
291-310.
|
|
|
|
|
|
|
A.Oda,
N.Yamaotsu,
and
S.Hirono
(2004).
Studies of binding modes of (S)-mephenytoin to wild types and mutants of cytochrome P450 2C19 and 2C9 using homology modeling and computational docking.
|
| |
Pharm Res,
21,
2270-2278.
|
|
|
|
|
|
|
E.E.Scott,
M.A.White,
Y.A.He,
E.F.Johnson,
C.D.Stout,
and
J.R.Halpert
(2004).
Structure of mammalian cytochrome P450 2B4 complexed with 4-(4-chlorophenyl)imidazole at 1.9-A resolution: insight into the range of P450 conformations and the coordination of redox partner binding.
|
| |
J Biol Chem,
279,
27294-27301.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
G.A.Schoch,
J.K.Yano,
M.R.Wester,
K.J.Griffin,
C.D.Stout,
and
E.F.Johnson
(2004).
Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site.
|
| |
J Biol Chem,
279,
9497-9503.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
J.K.Yano,
M.R.Wester,
G.A.Schoch,
K.J.Griffin,
C.D.Stout,
and
E.F.Johnson
(2004).
The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-A resolution.
|
| |
J Biol Chem,
279,
38091-38094.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
L.Xiao,
V.Madison,
A.S.Chau,
D.Loebenberg,
R.E.Palermo,
and
P.M.McNicholas
(2004).
Three-dimensional models of wild-type and mutated forms of cytochrome P450 14alpha-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding.
|
| |
Antimicrob Agents Chemother,
48,
568-574.
|
|
|
|
|
|
|
M.R.Wester,
J.K.Yano,
G.A.Schoch,
C.Yang,
K.J.Griffin,
C.D.Stout,
and
E.F.Johnson
(2004).
The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution.
|
| |
J Biol Chem,
279,
35630-35637.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
T.A.Clarke,
S.C.Im,
A.Bidwai,
and
L.Waskell
(2004).
The role of the length and sequence of the linker domain of cytochrome b5 in stimulating cytochrome P450 2B4 catalysis.
|
| |
J Biol Chem,
279,
36809-36818.
|
|
|
|
|
|
|
W.M.Atkins
(2004).
Implications of the allosteric kinetics of cytochrome P450s.
|
| |
Drug Discov Today,
9,
478-484.
|
|
|
|
|
|
|
E.E.Scott,
Y.A.He,
M.R.Wester,
M.A.White,
C.C.Chin,
J.R.Halpert,
E.F.Johnson,
and
C.D.Stout
(2003).
An open conformation of mammalian cytochrome P450 2B4 at 1.6-A resolution.
|
| |
Proc Natl Acad Sci U S A,
100,
13196-13201.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
S.Nagano,
H.Li,
H.Shimizu,
C.Nishida,
H.Ogura,
P.R.Ortiz de Montellano,
and
T.L.Poulos
(2003).
Crystal structures of epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P450epoK.
|
| |
J Biol Chem,
278,
44886-44893.
|
|
|
PDB codes:
|
|
|
|
|
|
|
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.
|
|
Links
