3wvs

<StructureSection load='3wvs' size='340' side='right'caption='[[3wvs]], [[Resolution|resolution]] 1.40&Aring;' scene=''>

<table><tr><td colspan='2'>[[3wvs]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WVS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WVS FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=RRM:(2E,4S,5S,6E,8E)-10-{(2R,3S,6S,8R,9S)-9-BUTYL-8-[(1E,3E)-4-CARBOXY-3-METHYLBUTA-1,3-DIEN-1-YL]-3-METHYL-1,7-DIOXASPIRO[5.5]UNDEC-2-YL}-5-HYDROXY-4,8-DIMETHYLDECA-2,6,8-TRIENOIC+ACID'>RRM</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3wvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wvs OCA], [https://pdbe.org/3wvs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wvs RCSB], [https://www.ebi.ac.uk/pdbsum/3wvs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wvs ProSAT]</span></td></tr>

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== Publication Abstract from PubMed ==

Numerous cytochrome P450s are involved in secondary metabolite biosynthesis. The biosynthetic gene cluster for reveromycin A (RM-A), which is a promising lead compound with anti-osteoclastic activity, also includes a P450 gene, revI. To understand the roles of P450revI, we comprehensively characterized the enzyme by genetic, kinetic, and structural studies. The revI gene disruptants (DeltarevI) resulted in accumulation of reveromycin T (RM-T), and revI gene complementation restored RM-A production, indicating that the physiological substrate of P450revI is RM-T. Indeed, the purified P450revI catalyzed the C18-hydroxylation of RM-T more efficiently than the other RM derivatives tested. Moreover, the 1.4-A resolution co-crystal structure of P450revI with RM-T revealed that the substrate binds the enzyme with a folded compact conformation for C18-hydroxylation. To address the structure-enzyme activity relationship, site-directed mutagenesis was performed in P450revI. Arg190Ala and Arg81Ala mutations, which abolished salt bridge formation with C1 and C24 carboxyl groups of RM-T, respectively, resulted in significant loss of enzyme activity. The interaction between Arg190 and the C1 carboxyl group of RM-T elucidated why P450revI was unable to catalyze both RM-T 1-methyl ester and RM-T 1-ethyl ester. Moreover, the accumulation of RM-T in DeltarevI mutants enabled us to characterize its biological activity. Our results show that RM-T had stronger anticancer activity and isoleucyl-tRNA synthetase inhibition than RM-A. However, RM-T showed much less anti-osteoclastic activity than RM-A, indicating that hemisuccinate moiety is important for the activity. Structure-based P450revI engineering for novel hydroxylation and subsequent hemisuccinylation will help facilitate the development of RM-derivatives with anti-osteoclast activity.

Structure-Function Analyses of Cytochrome P450revI Involved in Reveromycin A Biosynthesis and Evaluation of the Biological Activity of Its Substrate, Reveromycin T.,Takahashi S, Nagano S, Nogawa T, Kanoh N, Uramoto M, Kawatani M, Shimizu T, Miyazawa T, Shiro Y, Osada H J Biol Chem. 2014 Sep 25. pii: jbc.M114.598391. PMID:25258320<ref>PMID:25258320</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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<div class="pdbe-citations 3wvs" style="background-color:#fffaf0;"></div>

== References ==

<references/>

[[Category: Nagano, S]]

[[Category: Osada, H]]

[[Category: Shiro, Y]]

[[Category: Takahashi, S]]

[[Category: Oxidoreductase]]