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Article: Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding

TitleStructures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding
Authors
Issue Date2006
PublisherWiley-Blackwell Publishing, Inc.. The Journal's web site is located at http://www.proteinscience.org
Citation
Protein Science, 2006, v. 15 n. 4, p. 774-784 How to Cite?
AbstractMethicillin-resistant Staphylococcus aureus (MRSA) poses a major threat to human health, particularly through hospital acquired infection. The spread of MRSA means that novel targets are required to develop potential inhibitors to combat infections caused by such drug-resistant bacteria. Thymidylate kinase (TMK) is attractive as an antibacterial target as it is essential for providing components for DNA synthesis. Here, we report crystal structures of unliganded and thymidylate-bound forms of S. aureus thymidylate kinase (SaTMK). His-tagged and untagged SaTMK crystallize with differing lattice packing and show variations in conformational states for unliganded and thymidylate (TMP) bound forms. In addition to open and closed forms of SaTMK, an intermediate conformation inTMP binding is observed, in which the site is partially closed. Analysis of these structures indicates a sequence of events upon TMP binding, with helix α3 shifting position initially, followed by movement of α2 to close the substrate site. In addition, we observe significant conformational differences in the TMP-binding site in SaTMK as compared to available TMK structures from other bacterial species, Escherichia coli and Mycobacterium tuberculosis as well as human TMK. In SaTMK, Arg 48 is situated at the base of the TMP-binding site, close to the thymine ring, whereas a cis-proline occupies the equivalent position in other TMKs. The observed TMK structural differences mean that design of compounds highly specific for the S. aureus enzyme looks possible; such inhibitors could minimize the transfer of drug resistance between different bacterial species. Copyright © 2006 The Protein Society.
Persistent Identifierhttp://hdl.handle.net/10722/171742
ISSN
2015 Impact Factor: 3.039
2015 SCImago Journal Rankings: 2.029
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKotaka, Men_US
dc.contributor.authorDhaliwal, Ben_US
dc.contributor.authorRen, Jen_US
dc.contributor.authorNichols, CEen_US
dc.contributor.authorAngell, Ren_US
dc.contributor.authorLockyer, Men_US
dc.contributor.authorHawkins, ARen_US
dc.contributor.authorStammers, DKen_US
dc.date.accessioned2012-10-30T06:16:44Z-
dc.date.available2012-10-30T06:16:44Z-
dc.date.issued2006en_US
dc.identifier.citationProtein Science, 2006, v. 15 n. 4, p. 774-784en_US
dc.identifier.issn0961-8368en_US
dc.identifier.urihttp://hdl.handle.net/10722/171742-
dc.description.abstractMethicillin-resistant Staphylococcus aureus (MRSA) poses a major threat to human health, particularly through hospital acquired infection. The spread of MRSA means that novel targets are required to develop potential inhibitors to combat infections caused by such drug-resistant bacteria. Thymidylate kinase (TMK) is attractive as an antibacterial target as it is essential for providing components for DNA synthesis. Here, we report crystal structures of unliganded and thymidylate-bound forms of S. aureus thymidylate kinase (SaTMK). His-tagged and untagged SaTMK crystallize with differing lattice packing and show variations in conformational states for unliganded and thymidylate (TMP) bound forms. In addition to open and closed forms of SaTMK, an intermediate conformation inTMP binding is observed, in which the site is partially closed. Analysis of these structures indicates a sequence of events upon TMP binding, with helix α3 shifting position initially, followed by movement of α2 to close the substrate site. In addition, we observe significant conformational differences in the TMP-binding site in SaTMK as compared to available TMK structures from other bacterial species, Escherichia coli and Mycobacterium tuberculosis as well as human TMK. In SaTMK, Arg 48 is situated at the base of the TMP-binding site, close to the thymine ring, whereas a cis-proline occupies the equivalent position in other TMKs. The observed TMK structural differences mean that design of compounds highly specific for the S. aureus enzyme looks possible; such inhibitors could minimize the transfer of drug resistance between different bacterial species. Copyright © 2006 The Protein Society.en_US
dc.languageengen_US
dc.publisherWiley-Blackwell Publishing, Inc.. The Journal's web site is located at http://www.proteinscience.orgen_US
dc.relation.ispartofProtein Scienceen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshLigandsen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshNucleoside-Phosphate Kinase - Chemistry - Genetics - Isolation & Purification - Metabolismen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshProtein Conformationen_US
dc.subject.meshProtein Structure, Secondaryen_US
dc.subject.meshStaphylococcus Aureus - Enzymology - Metabolismen_US
dc.subject.meshSubstrate Specificityen_US
dc.titleStructures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate bindingen_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.doi10.1110/ps.052002406en_US
dc.identifier.pmid16522804-
dc.identifier.scopuseid_2-s2.0-33645508875en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33645508875&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume15en_US
dc.identifier.issue4en_US
dc.identifier.spage774en_US
dc.identifier.epage784en_US
dc.identifier.isiWOS:000236734200011-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridKotaka, M=6604073578en_US
dc.identifier.scopusauthoridDhaliwal, B=6602733569en_US
dc.identifier.scopusauthoridRen, J=7403083572en_US
dc.identifier.scopusauthoridNichols, CE=7202395045en_US
dc.identifier.scopusauthoridAngell, R=7006304705en_US
dc.identifier.scopusauthoridLockyer, M=36947976500en_US
dc.identifier.scopusauthoridHawkins, AR=7102975292en_US
dc.identifier.scopusauthoridStammers, DK=34573122600en_US
dc.identifier.citeulike546445-

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