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PDBsum entry 1suo
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Oxidoreductase
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PDB id
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1suo
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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E.E.Scott,
M.A.White,
Y.A.He,
E.F.Johnson,
C.D.Stout,
J.R.Halpert.
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Ref.
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J Biol Chem, 2004,
279,
27294-27301.
[DOI no: ]
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PubMed id
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Abstract
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A 1.9-A molecular structure of the microsomal cytochrome P450 2B4 with the
specific inhibitor 4-(4-chlorophenyl)imidazole (CPI) in the active site was
determined by x-ray crystallography. In contrast to the previous experimentally
determined 2B4 structure, this complex adopted a closed conformation similar to
that observed for the mammalian 2C enzymes. The differences between the open and
closed structures of 2B4 were primarily limited to the lid domain of helices F
through G, helices B' and C, the N terminus of helix I, and the beta(4) region.
These large-scale conformational changes were generally due to the relocation of
conserved structural elements toward each other with remarkably little
remodeling at the secondary structure level. For example, the F' and G' helices
were maintained with a sharp turn between them but are placed to form the
exterior ceiling of the active site in the CPI complex. CPI was closely
surrounded by residues from substrate recognition sites 1, 4, 5, and 6 to form a
small, isolated hydrophobic cavity. The switch from open to closed conformation
dramatically relocated helix C to a more proximal position. As a result, heme
binding interactions were altered, and the putative NADPH-cytochrome P450
reductase binding site was reformed. This suggests a structural mechanism
whereby ligand-induced conformational changes may coordinate catalytic activity.
Comparison of the 2B4/CPI complex with the open 2B4 structure yields insights
into the dynamics involved in substrate access, tight inhibitor binding, and
coordination of substrate and redox partner binding.
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Figure 2.
Divergent (walleye) stereo view of cytochrome P450
2B4dH(H226Y) with CPI bound. The sequence can be traced from the
blue N terminus to the red C terminus. Major helices and termini
are labeled. Heme and CPI are shown in red and cyan sticks,
respectively. Images generated using PyMOL (www.pymol.org) (41)
unless otherwise credited.
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Figure 7.
Changes in the position of the C helix and heme ligation upon
CPI binding shown in divergent (walleye) stereo. Residues in
helix C (ribbon) alter positions significantly between the 2B4
open (green) and the CPI closed (blue) conformations, resulting
in the loss of a hydrogen bond to the D ring propionate in the
open conformation. Hydrogen bonds between the D ring propionate
and helix C residues are indicated by dashed lines. Residues
Arg-98 (R98), Ser-430 (S430), Arg-434 (R434), and His-369 (H369)
have smaller changes in their positions and are labeled once
near the base of the side chain.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
27294-27301)
copyright 2004.
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Secondary reference #1
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Title
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An open conformation of mammalian cytochrome p450 2b4 at 1.6-A resolution.
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Authors
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E.E.Scott,
Y.A.He,
M.R.Wester,
M.A.White,
C.C.Chin,
J.R.Halpert,
E.F.Johnson,
C.D.Stout.
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Ref.
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Proc Natl Acad Sci U S A, 2003,
100,
13196-13201.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. The 2B4 structure and comparison with 2C5. (A) P450
2B4 is oriented to view the large cleft from the protein surface
to the heme. The sequence can be traced starting at the blue N
terminus and ending at the red C terminus. (B and C) Comparison
of 2B4 (B) and 2C5/3LV (1N6B [PDB]
) (C) structures. Residues with the highest rms deviations
between the two structures include 2B4 residues 37-50 (helix A'
and adjacent residues, magenta), residues 92-140 (helix B C
terminus to helix D N terminus, blue), residues 206-250
(C-terminal turn of helix F through helix G, purple), residues
275-300 (loop between helices H and I encompassing a
three-residue insertion in 2B4 relative to 2C5 and N-terminal
half of helix I, orange), and 474-479 (  turn between L' and [3-2],
gray). Excluding these residues, the rms deviation of 324 C^
 atoms between 2B4 and
2C5 is 1.08 Å. The heme group is shown as a stick figure,
and the iron is shown as a red sphere. N and C termini are
labeled. Unless otherwise noted, molecular figures were
generated by using PYMOL (28).
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Figure 2.
Fig. 2. Comparison of structural elements composing the 2B4
cleft. (A) Clefts in the mammalian 2B4 (green) and the bacterial
154C1 (PDB ID code 1GWI [PDB]
, blue) P450s are composed of similar structural elements. (B)
In 2B4 (green) helices, F' and G' flex away from the B' helix,
whereas in 2C5 (yellow), they extend to form the roof of the
active site. For clarity, only the regions including helices B
through D, F through G, and I are shown. The heme is shown as a
stick figure.
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Secondary reference #2
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Title
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A truncation of 2b subfamily cytochromes p450 yields increased expression levels, Increased solubility, And decreased aggregation while retaining function.
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Authors
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E.E.Scott,
M.Spatzenegger,
J.R.Halpert.
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Ref.
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Arch Biochem Biophys, 2001,
395,
57-68.
[DOI no: ]
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PubMed id
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