A tetrameric structure is not essential for activity in dihydrodipicolinate synthase (DHDPS) from Mycobacterium tuberculosis

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dc.contributor.author Evans, Genevieve en
dc.contributor.author Schuldt, L en
dc.contributor.author Griffin, MDW en
dc.contributor.author Devenish, SRA en
dc.contributor.author Pearce, FG en
dc.contributor.author Perugini, MA en
dc.contributor.author Dobson, Renwick en
dc.contributor.author Jameson, GB en
dc.contributor.author Weiss, MS en
dc.contributor.author Gerrard, Juliet en
dc.date.accessioned 2012-03-04T22:40:15Z en
dc.date.issued 2011-08-15 en
dc.identifier.citation Archives of Biochemistry and Biophysics 512(2):154-159 15 Aug 2011 en
dc.identifier.issn 0003-9861 en
dc.identifier.uri http://hdl.handle.net/2292/12765 en
dc.description.abstract Dihydrodipicolinate synthase (DHDPS) is a validated antibiotic target for which a new approach to inhibitor design has been proposed: disrupting native tetramer formation by targeting the dimer–dimer interface. In this study, rational design afforded a variant of Mycobacterium tuberculosis, Mtb-DHDPS-A204R, with disrupted quaternary structure. X-ray crystallography (at a resolution of 2.1 Å) revealed a dimeric protein with an identical fold and active-site structure to the tetrameric wild-type enzyme. Analytical ultracentrifugation confirmed the dimeric structure in solution, yet the dimeric mutant has similar activity to the wild-type enzyme. Although the affinity for both substrates was somewhat decreased, the high catalytic competency of the enzyme was surprising in the light of previous results showing that dimeric variants of the Escherichia coli and Bacillus anthracis DHDPS enzymes have dramatically reduced activity compared to their wild-type tetrameric counterparts. These results suggest that Mtb-DHDPS-A204R is similar to the natively dimeric enzyme from Staphylococcus aureus, and highlight our incomplete understanding of the role played by oligomerisation in relating protein structure and function. en
dc.language EN en
dc.publisher Elsevier Science en
dc.relation.ispartofseries Archives of Biochemistry and Biophysics en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0003-9861/ en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.subject DHDPS en
dc.subject Dihydrodipicolinate synthase en
dc.subject Quaternary structure en
dc.subject Tuberculosis en
dc.subject ESCHERICHIA-COLI en
dc.subject RESOLUTION en
dc.subject SMEGMATIS en
dc.subject PROTEINS en
dc.subject LYSINE en
dc.subject REFINEMENT en
dc.subject EVOLUTION en
dc.subject MUTANTS en
dc.title A tetrameric structure is not essential for activity in dihydrodipicolinate synthase (DHDPS) from Mycobacterium tuberculosis en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.abb.2011.05.014 en
pubs.issue 2 en
pubs.begin-page 154 en
pubs.volume 512 en
dc.rights.holder Copyright: Elsevier Science Inc en
dc.identifier.pmid 21672512 en
pubs.end-page 159 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 223134 en
pubs.org-id Science en
pubs.org-id Biological Sciences en
pubs.record-created-at-source-date 2012-02-15 en
pubs.dimensions-id 21672512 en

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