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Article: A zinc-binding site by negative selection induces metallodrug susceptibility in an essential chaperonin

TitleA zinc-binding site by negative selection induces metallodrug susceptibility in an essential chaperonin
Authors
Issue Date2010
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, 2010, v. 107 n. 11, p. 4943-4948 How to Cite?
AbstractGroES is an indispensable chaperonin virtually found throughout all life forms. Consequently, mutations of this protein must be critically scrutinized by natural selection. Nevertheless, the homolog from a potentially virulent gastric pathogen, Helicobacter pylori, strikingly features a histidine/cysteine-rich C terminus that shares no significant homology with other family members. Additionally, three more (H45, C51, and C53) are uniquely present in its apical domain. The statistical analyses show that these residues may have originated from negative selection, presumably driven by either dependent or independent amino acid mutations. In the absence of the C-terminal metal-binding domain, the mutant protein still exhibits a substantial capacity for zinc binding in vivo. The biochemical properties of site-directed mutants indicate that H45, C51, and C53 make up an oxidation-sensitive zinc-binding site that may donate the bound metal to a zinc acceptor. Of interest, bismuth antiulcer drugs strongly bind at this site (Kd of approximately 7 × 10-26 M), replacing the bound zinc and consequently inducing the disruption of the quaternary structure. Because biological features by negative selection are usually inert to change during evolution, this study sheds light on a promising field whereby medicines can be designed or improved to specifically target the residues that uniquely evolved in pathogenic proteins so as to retard the emergence of drug resistance.
Persistent Identifierhttp://hdl.handle.net/10722/168445
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCun, Sen_US
dc.contributor.authorSun, Hen_US
dc.date.accessioned2012-10-08T03:19:01Z-
dc.date.available2012-10-08T03:19:01Z-
dc.date.issued2010en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 11, p. 4943-4948en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/168445-
dc.description.abstractGroES is an indispensable chaperonin virtually found throughout all life forms. Consequently, mutations of this protein must be critically scrutinized by natural selection. Nevertheless, the homolog from a potentially virulent gastric pathogen, Helicobacter pylori, strikingly features a histidine/cysteine-rich C terminus that shares no significant homology with other family members. Additionally, three more (H45, C51, and C53) are uniquely present in its apical domain. The statistical analyses show that these residues may have originated from negative selection, presumably driven by either dependent or independent amino acid mutations. In the absence of the C-terminal metal-binding domain, the mutant protein still exhibits a substantial capacity for zinc binding in vivo. The biochemical properties of site-directed mutants indicate that H45, C51, and C53 make up an oxidation-sensitive zinc-binding site that may donate the bound metal to a zinc acceptor. Of interest, bismuth antiulcer drugs strongly bind at this site (Kd of approximately 7 × 10-26 M), replacing the bound zinc and consequently inducing the disruption of the quaternary structure. Because biological features by negative selection are usually inert to change during evolution, this study sheds light on a promising field whereby medicines can be designed or improved to specifically target the residues that uniquely evolved in pathogenic proteins so as to retard the emergence of drug resistance.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.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAmino Acid Substitution - Geneticsen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshBinding, Competitiveen_US
dc.subject.meshBismuth - Metabolismen_US
dc.subject.meshChaperonin 10 - Chemistry - Metabolismen_US
dc.subject.meshCysteine - Metabolismen_US
dc.subject.meshDrug Resistance - Geneticsen_US
dc.subject.meshEscherichia Coli - Growth & Developmenten_US
dc.subject.meshHelicobacter Pylori - Metabolismen_US
dc.subject.meshHistidine - Metabolismen_US
dc.subject.meshKineticsen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMutant Proteins - Chemistry - Metabolismen_US
dc.subject.meshOxidation-Reductionen_US
dc.subject.meshProtein Structure, Quaternaryen_US
dc.subject.meshProtein Structure, Tertiaryen_US
dc.subject.meshSelection, Geneticen_US
dc.subject.meshZinc - Metabolismen_US
dc.titleA zinc-binding site by negative selection induces metallodrug susceptibility in an essential chaperoninen_US
dc.typeArticleen_US
dc.identifier.emailSun, H:hsun@hkucc.hku.hken_US
dc.identifier.authoritySun, H=rp00777en_US
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1073/pnas.0913970107en_US
dc.identifier.pmid20194796-
dc.identifier.pmcidPMC2841863-
dc.identifier.scopuseid_2-s2.0-77950433102en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77950433102&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume107en_US
dc.identifier.issue11en_US
dc.identifier.spage4943en_US
dc.identifier.epage4948en_US
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000275714300028-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridCun, S=24467307200en_US
dc.identifier.scopusauthoridSun, H=7404827446en_US

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