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PDBsum entry 1n4g
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Oxidoreductase
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PDB id
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1n4g
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Contents |
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* Residue conservation analysis
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PDB id:
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Oxidoreductase
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Title:
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Structure of cyp121, a mycobacterial p450, in complex with iodopyrazole
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Structure:
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Cytochrome p450 121. Chain: a. Fragment: p450 cyp 121. Synonym: p450 mt2. Engineered: yes
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Source:
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Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: cyp121 or rv2276 or mt2336 or mtcy339.34c. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Biol. unit:
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Dimer (from
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Resolution:
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1.80Å
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R-factor:
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0.206
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R-free:
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0.217
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Authors:
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D.Leys,C.G.Mowat,K.J.Mclean,A.Richmond,S.K.Chapman,M.D.Walkinshaw, A.W.Munro,Tb Structural Genomics Consortium (Tbsgc)
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Key ref:
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D.Leys
et al.
(2003).
Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 A reveals novel features of cytochrome P450.
J Biol Chem,
278,
5141-5147.
PubMed id:
DOI:
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Date:
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31-Oct-02
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Release date:
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04-Feb-03
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PROCHECK
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Headers
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References
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P9WPP7
(CP121_MYCTU) -
Mycocyclosin synthase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
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Seq:
Struc:
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396 a.a.
392 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.1.14.19.70
- mycocyclosin synthase.
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Reaction:
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cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced [2Fe-2S]-[ferredoxin] + O2 + 2 H+ = mycoclysin + 2 oxidized [2Fe-2S]-[ferredoxin] + 2 H2O
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cyclo(L-tyrosyl-L-tyrosyl)
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+
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2
×
reduced [2Fe-2S]-[ferredoxin]
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+
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O2
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+
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2
×
H(+)
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=
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mycoclysin
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+
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2
×
oxidized [2Fe-2S]-[ferredoxin]
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+
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2
×
H2O
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Cofactor:
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Heme-thiolate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Biol Chem
278:5141-5147
(2003)
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PubMed id:
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Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 A reveals novel features of cytochrome P450.
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D.Leys,
C.G.Mowat,
K.J.McLean,
A.Richmond,
S.K.Chapman,
M.D.Walkinshaw,
A.W.Munro.
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ABSTRACT
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The first structure of a P450 to an atomic resolution of 1.06 A has been solved
for CYP121 from Mycobacterium tuberculosis. A comparison with P450 EryF
(CYP107A1) reveals a remarkable overall similarity in fold with major
differences residing in active site structural elements. The high resolution
obtained allows visualization of several unusual aspects. The heme cofactor is
bound in two distinct conformations while being notably kinked in one pyrrole
group due to close interaction with the proline residue (Pro(346)) immediately
following the heme iron-ligating cysteine (Cys(345)). The active site is
remarkably rigid in comparison with the remainder of the structure,
notwithstanding the large cavity volume of 1350 A(3). The region immediately
surrounding the distal water ligand is remarkable in several aspects. Unlike
other bacterial P450s, the I helix shows no deformation, similar to mammalian
CYP2C5. In addition, the positively charged Arg(386) is located immediately
above the heme plane, dominating the local structure. Putative proton relay
pathways from protein surface to heme (converging at Ser(279)) are identified.
Most interestingly, the electron density indicates weak binding of a dioxygen
molecule to the P450. This structure provides a basis for rational design of
putative antimycobacterial agents.
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Selected figure(s)
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Figure 3.
Fig. 3. Structural comparison of CYP121 with CYP107A1
(P450 EryF) from S. erythraea. Shown is a stereo view of the
overlay of Mtb CYP121 (dark gray) with S. erythraea CYP107A1
(light gray). Loops and secondary elements lining the active
site cavity are clearly more divergent than the remainder of the
structure.
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Figure 5.
Fig. 5. Hydrogen bonding pattern in the CYP121 I helix.
Residues of the CYP121 I helix close to the heme group are shown
in gray ball and stick mode. All bacterial cytochromes P450 show
a severe disruption of the hydrogen bonding pattern between Ala
233 and Ser237 (CYP121 numbering). Remarkably, this distortion
is not seen in CYP121 in the vicinity of the relevant amino acid
(Ser237), similar to the mammalian CYP2C5 structure (9).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
5141-5147)
copyright 2003.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.J.Whitehouse,
W.Yang,
J.A.Yorke,
B.C.Rowlatt,
A.J.Strong,
C.F.Blanford,
S.G.Bell,
M.Bartlam,
L.L.Wong,
and
Z.Rao
(2010).
Structural basis for the properties of two single-site proline mutants of CYP102A1 (P450BM3).
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Chembiochem,
11,
2549-2556.
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H.Ouellet,
J.B.Johnston,
and
P.R.Ortiz de Montellano
(2010).
The Mycobacterium tuberculosis cytochrome P450 system.
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Arch Biochem Biophys,
493,
82-95.
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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.
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Plant Mol Biol,
74,
167-181.
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T.C.Pochapsky,
S.Kazanis,
and
M.Dang
(2010).
Conformational plasticity and structure/function relationships in cytochromes P450.
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Antioxid Redox Signal,
13,
1273-1296.
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C.J.Whitehouse,
S.G.Bell,
W.Yang,
J.A.Yorke,
C.F.Blanford,
A.J.Strong,
E.J.Morse,
M.Bartlam,
Z.Rao,
and
L.L.Wong
(2009).
A highly active single-mutation variant of P450BM3 (CYP102A1).
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Chembiochem,
10,
1654-1656.
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PDB code:
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D.Baniulis,
E.Yamashita,
J.P.Whitelegge,
A.I.Zatsman,
M.P.Hendrich,
S.S.Hasan,
C.M.Ryan,
and
W.A.Cramer
(2009).
Structure-Function, Stability, and Chemical Modification of the Cyanobacterial Cytochrome b6f Complex from Nostoc sp. PCC 7120.
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J Biol Chem,
284,
9861-9869.
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PDB code:
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F.Sabbadin,
R.Jackson,
K.Haider,
G.Tampi,
J.P.Turkenburg,
S.Hart,
N.C.Bruce,
and
G.Grogan
(2009).
The 1.5-A structure of XplA-heme, an unusual cytochrome P450 heme domain that catalyzes reductive biotransformation of royal demolition explosive.
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J Biol Chem,
284,
28467-28475.
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PDB codes:
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H.Ouellet,
J.Lang,
M.Couture,
and
P.R.Ortiz de Montellano
(2009).
Reaction of Mycobacterium tuberculosis cytochrome P450 enzymes with nitric oxide.
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Biochemistry,
48,
863-872.
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J.B.Johnston,
P.M.Kells,
L.M.Podust,
and
P.R.Ortiz de Montellano
(2009).
Biochemical and structural characterization of CYP124: a methyl-branched lipid omega-hydroxylase from Mycobacterium tuberculosis.
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Proc Natl Acad Sci U S A,
106,
20687-20692.
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PDB codes:
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K.J.McLean,
P.Lafite,
C.Levy,
M.R.Cheesman,
N.Mast,
I.A.Pikuleva,
D.Leys,
and
A.W.Munro
(2009).
The Structure of Mycobacterium tuberculosis CYP125: molecular basis for cholesterol binding in a P450 needed for host infection.
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J Biol Chem,
284,
35524-35533.
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PDB codes:
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P.Belin,
M.H.Le Du,
A.Fielding,
O.Lequin,
M.Jacquet,
J.B.Charbonnier,
A.Lecoq,
R.Thai,
M.Courçon,
C.Masson,
C.Dugave,
R.Genet,
J.L.Pernodet,
and
M.Gondry
(2009).
Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in Mycobacterium tuberculosis.
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Proc Natl Acad Sci U S A,
106,
7426-7431.
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S.Balaz
(2009).
Modeling kinetics of subcellular disposition of chemicals.
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Chem Rev,
109,
1793-1899.
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S.P.de Visser,
L.Tahsini,
and
W.Nam
(2009).
How does the axial ligand of cytochrome P450 biomimetics influence the regioselectivity of aliphatic versus aromatic hydroxylation?
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Chemistry,
15,
5577-5587.
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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).
Characterization of active site structure in CYP121. A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv.
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J Biol Chem,
283,
33406-33416.
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PDB code:
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N.Oezguen,
S.Kumar,
A.Hindupur,
W.Braun,
B.K.Muralidhara,
and
J.R.Halpert
(2008).
Identification and analysis of conserved sequence motifs in cytochrome P450 family 2. Functional and structural role of a motif 187RFDYKD192 in CYP2B enzymes.
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J Biol Chem,
283,
21808-21816.
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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.
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Nat Prod Rep,
24,
585-609.
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C.Berne,
D.Pignol,
J.Lavergne,
and
D.Garcia
(2007).
CYP201A2, a cytochrome P450 from Rhodopseudomonas palustris, plays a key role in the biodegradation of tributyl phosphate.
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Appl Microbiol Biotechnol,
77,
135-144.
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M.A.Carrondo,
I.Bento,
P.M.Matias,
and
P.F.Lindley
(2007).
Crystallographic evidence for dioxygen interactions with iron proteins.
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J Biol Inorg Chem,
12,
429-442.
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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.
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Trends Microbiol,
14,
220-228.
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M.J.de Groot
(2006).
Designing better drugs: predicting cytochrome P450 metabolism.
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Drug Discov Today,
11,
601-606.
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S.Hasan,
S.Daugelat,
P.S.Rao,
and
M.Schreiber
(2006).
Prioritizing genomic drug targets in pathogens: application to Mycobacterium tuberculosis.
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PLoS Comput Biol,
2,
e61.
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Z.Ahmad,
S.Sharma,
and
G.K.Khuller
(2006).
Azole antifungals as novel chemotherapeutic agents against murine tuberculosis.
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FEMS Microbiol Lett,
261,
181-186.
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H.E.Seward,
H.M.Girvan,
and
A.W.Munro
(2005).
Cytochrome P450s: creating novel ligand sets.
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Dalton Trans,
(),
3419-3426.
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J.Mestres
(2005).
Structure conservation in cytochromes P450.
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Proteins,
58,
596-609.
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Y.Zhang
(2005).
The magic bullets and tuberculosis drug targets.
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Annu Rev Pharmacol Toxicol,
45,
529-564.
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L.M.Podust,
H.Bach,
Y.Kim,
D.C.Lamb,
M.Arase,
D.H.Sherman,
S.L.Kelly,
and
M.R.Waterman
(2004).
Comparison of the 1.85 A structure of CYP154A1 from Streptomyces coelicolor A3(2) with the closely related CYP154C1 and CYPs from antibiotic biosynthetic pathways.
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Protein Sci,
13,
255-268.
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PDB code:
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O.Pylypenko,
and
I.Schlichting
(2004).
Structural aspects of ligand binding to and electron transfer in bacterial and fungal P450s.
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Annu Rev Biochem,
73,
991.
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C.V.Smith,
and
J.C.Sacchettini
(2003).
Mycobacterium tuberculosis: a model system for structural genomics.
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Curr Opin Struct Biol,
13,
658-664.
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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.
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Links
