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Article: Structural basis for the design of potent and species-specific inhibitors of 3-hydroxy-3-methylglutaryl CoA synthases

TitleStructural basis for the design of potent and species-specific inhibitors of 3-hydroxy-3-methylglutaryl CoA synthases
Authors
Issue Date2006
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2006, v. 103 n. 31, p. 11491-11496 How to Cite?
Abstract3-Hydroxy-3-methylglutaryl CoA synthase (HMGS) catalyzes the first committed step in the mevalonate metabolic pathway for isoprenoid biosynthesis and serves as an alternative target for cholesterol-lowering and antibiotic drugs. We have determined a previously undescribed crystal structure of a eukaryotic HMGS bound covalently to a potent and specific inhibitor F-244 [(E,E)-11-[3-(hydroxymethyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2, 4-undecadienenoic acid]. Given the accessibility of synthetic analogs of the F-244 natural product, this inhibited eukaryotic HMGS structure serves as a necessary starting point for structure-based methods that may improve the potency and species-specific selectivity of the next generation of F-244 analogs designed to target particular eukaryotic and prokaryotic HMGS. © 2006 by The National Academy of Sciences of the USA.
Persistent Identifierhttp://hdl.handle.net/10722/178951
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorPojer, Fen_US
dc.contributor.authorFerrer, JLen_US
dc.contributor.authorRichard, SBen_US
dc.contributor.authorNagegowda, DAen_US
dc.contributor.authorChye, MLen_US
dc.contributor.authorBach, TJen_US
dc.contributor.authorNoel, JPen_US
dc.date.accessioned2012-12-19T09:51:00Z-
dc.date.available2012-12-19T09:51:00Z-
dc.date.issued2006en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2006, v. 103 n. 31, p. 11491-11496en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/178951-
dc.description.abstract3-Hydroxy-3-methylglutaryl CoA synthase (HMGS) catalyzes the first committed step in the mevalonate metabolic pathway for isoprenoid biosynthesis and serves as an alternative target for cholesterol-lowering and antibiotic drugs. We have determined a previously undescribed crystal structure of a eukaryotic HMGS bound covalently to a potent and specific inhibitor F-244 [(E,E)-11-[3-(hydroxymethyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2, 4-undecadienenoic acid]. Given the accessibility of synthetic analogs of the F-244 natural product, this inhibited eukaryotic HMGS structure serves as a necessary starting point for structure-based methods that may improve the potency and species-specific selectivity of the next generation of F-244 analogs designed to target particular eukaryotic and prokaryotic HMGS. © 2006 by The National Academy of Sciences of the USA.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshEnzyme Inhibitors - Chemistry - Metabolismen_US
dc.subject.meshFatty Acids, Unsaturated - Chemistry - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshHydroxymethylglutaryl-Coa Synthase - Antagonists & Inhibitors - Chemistry - Metabolismen_US
dc.subject.meshLactones - Chemistry - Metabolismen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMustard Plant - Enzymologyen_US
dc.subject.meshPlant Proteins - Antagonists & Inhibitors - Chemistry - Metabolismen_US
dc.subject.meshProtein Structure, Tertiaryen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.titleStructural basis for the design of potent and species-specific inhibitors of 3-hydroxy-3-methylglutaryl CoA synthasesen_US
dc.typeArticleen_US
dc.identifier.emailChye, ML: mlchye@hkucc.hku.hken_US
dc.identifier.authorityChye, ML=rp00687en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.0604935103en_US
dc.identifier.pmid16864776-
dc.identifier.scopuseid_2-s2.0-33746835442en_US
dc.identifier.hkuros117621-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33746835442&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume103en_US
dc.identifier.issue31en_US
dc.identifier.spage11491en_US
dc.identifier.epage11496en_US
dc.identifier.isiWOS:000239616400014-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridPojer, F=12776271100en_US
dc.identifier.scopusauthoridFerrer, JL=35473126500en_US
dc.identifier.scopusauthoridRichard, SB=7102035509en_US
dc.identifier.scopusauthoridNagegowda, DA=8709830800en_US
dc.identifier.scopusauthoridChye, ML=7003905460en_US
dc.identifier.scopusauthoridBach, TJ=24786011400en_US
dc.identifier.scopusauthoridNoel, JP=7201615808en_US

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