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PDBsum entry 1q5e
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Oxidoreductase
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PDB id
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1q5e
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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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Crystal structures of epothilone d-Bound, Epothilone b-Bound, And substrate-Free forms of cytochrome p450epok.
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Authors
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S.Nagano,
H.Li,
H.Shimizu,
C.Nishida,
H.Ogura,
P.R.Ortiz de montellano,
T.L.Poulos.
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Ref.
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J Biol Chem, 2003,
278,
44886-44893.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
44886-44893)
copyright 2003.
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