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Article: Induced-fit upon Ligand Binding Revealed by Crystal Structures of the Hot-dog Fold Thioesterase in Dynemicin Biosynthesis

TitleInduced-fit upon Ligand Binding Revealed by Crystal Structures of the Hot-dog Fold Thioesterase in Dynemicin Biosynthesis
Authors
Issue Date2010
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
Citation
Journal Of Molecular Biology, 2010, v. 404 n. 2, p. 291-306 How to Cite?
AbstractDynemicins are structurally related 10-membered enediyne natural products isolated from Micromonospora chernisa with potent antitumor and antibiotic activity. The early biosynthetic steps of the enediyne moiety of dynemicins are catalyzed by an iterative polyketide synthase (DynE8) and a thioesterase (DynE7). Recent studies indicate that the function of DynE7 is to off-load the linear biosynthetic intermediate assembled on DynE8. Here, we report crystal structures of DynE7 in its free form at 2.7 Å resolution and of DynE7 in complex with the DynE8-produced all-trans pentadecen-2-one at 2.1 Å resolution. These crystal structures reveal that upon ligand binding, significant conformational changes throughout the substrate-binding tunnel result in an expanded tunnel that traverses an entire monomer of the tetrameric DynE7 protein. The enlarged inner segment of the channel binds the carbonyl-conjugated polyene mainly through hydrophobic interactions, whereas the putative catalytic residues are located in the outer segment of the channel. The crystallographic information reinforces an unusual catalytic mechanism that involves a strictly conserved arginine residue for this subfamily of hot-dog fold thioesterases, distinct from the typical mechanism for hot-dog fold thioesterases that utilizes an acidic residue for catalysis. © 2010 Elsevier Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/171784
ISSN
2015 Impact Factor: 4.517
2015 SCImago Journal Rankings: 3.002
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLiew, CWen_US
dc.contributor.authorSharff, Aen_US
dc.contributor.authorKotaka, Men_US
dc.contributor.authorKong, Ren_US
dc.contributor.authorSun, Hen_US
dc.contributor.authorQureshi, Ien_US
dc.contributor.authorBricogne, Gen_US
dc.contributor.authorLiang, ZXen_US
dc.contributor.authorLescar, Jen_US
dc.date.accessioned2012-10-30T06:17:04Z-
dc.date.available2012-10-30T06:17:04Z-
dc.date.issued2010en_US
dc.identifier.citationJournal Of Molecular Biology, 2010, v. 404 n. 2, p. 291-306en_US
dc.identifier.issn0022-2836en_US
dc.identifier.urihttp://hdl.handle.net/10722/171784-
dc.description.abstractDynemicins are structurally related 10-membered enediyne natural products isolated from Micromonospora chernisa with potent antitumor and antibiotic activity. The early biosynthetic steps of the enediyne moiety of dynemicins are catalyzed by an iterative polyketide synthase (DynE8) and a thioesterase (DynE7). Recent studies indicate that the function of DynE7 is to off-load the linear biosynthetic intermediate assembled on DynE8. Here, we report crystal structures of DynE7 in its free form at 2.7 Å resolution and of DynE7 in complex with the DynE8-produced all-trans pentadecen-2-one at 2.1 Å resolution. These crystal structures reveal that upon ligand binding, significant conformational changes throughout the substrate-binding tunnel result in an expanded tunnel that traverses an entire monomer of the tetrameric DynE7 protein. The enlarged inner segment of the channel binds the carbonyl-conjugated polyene mainly through hydrophobic interactions, whereas the putative catalytic residues are located in the outer segment of the channel. The crystallographic information reinforces an unusual catalytic mechanism that involves a strictly conserved arginine residue for this subfamily of hot-dog fold thioesterases, distinct from the typical mechanism for hot-dog fold thioesterases that utilizes an acidic residue for catalysis. © 2010 Elsevier Ltd.en_US
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmben_US
dc.relation.ispartofJournal of Molecular Biologyen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAntibiotics, Antineoplastic - Biosynthesis - Chemistryen_US
dc.subject.meshCatalysisen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshEnediynes - Chemistry - Metabolismen_US
dc.subject.meshLigandsen_US
dc.subject.meshMicromonospora - Genetics - Metabolismen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMultienzyme Complexes - Chemistryen_US
dc.subject.meshMutagenesis, Site-Directeden_US
dc.subject.meshPolyketide Synthases - Chemistry - Genetics - Metabolismen_US
dc.subject.meshProtein Foldingen_US
dc.subject.meshProtein Interaction Domains And Motifsen_US
dc.subject.meshProtein Structure, Quaternaryen_US
dc.subject.meshRecombinant Proteins - Chemistry - Genetics - Metabolismen_US
dc.subject.meshSequence Homology, Amino Aciden_US
dc.subject.meshThiolester Hydrolases - Chemistry - Genetics - Metabolismen_US
dc.titleInduced-fit upon Ligand Binding Revealed by Crystal Structures of the Hot-dog Fold Thioesterase in Dynemicin Biosynthesisen_US
dc.typeArticleen_US
dc.identifier.emailKotaka, M:masayo@hku.hken_US
dc.identifier.authorityKotaka, M=rp00293en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.jmb.2010.09.041en_US
dc.identifier.pmid20888341-
dc.identifier.scopuseid_2-s2.0-78349306683en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78349306683&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume404en_US
dc.identifier.issue2en_US
dc.identifier.spage291en_US
dc.identifier.epage306en_US
dc.identifier.isiWOS:000285168600009-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridLiew, CW=24437011000en_US
dc.identifier.scopusauthoridSharff, A=6602362262en_US
dc.identifier.scopusauthoridKotaka, M=6604073578en_US
dc.identifier.scopusauthoridKong, R=55107990500en_US
dc.identifier.scopusauthoridSun, H=26968179900en_US
dc.identifier.scopusauthoridQureshi, I=14623211700en_US
dc.identifier.scopusauthoridBricogne, G=7003638909en_US
dc.identifier.scopusauthoridLiang, ZX=23668102800en_US
dc.identifier.scopusauthoridLescar, J=6603844493en_US
dc.identifier.citeulike7983325-

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