Show simple item record

dc.contributor.authorNebl, S
dc.contributor.authorAlwan, WS
dc.contributor.authorWilliams, ML
dc.contributor.authorSharma, G
dc.contributor.authorTaylor, A
dc.contributor.authorDoak, BC
dc.contributor.authorWilde, KL
dc.contributor.authorMcMahon, RM
dc.contributor.authorHalili, MA
dc.contributor.authorMartin, JL
dc.contributor.authorCapuano, B
dc.contributor.authorFenwick, RB
dc.contributor.authorMohanty, B
dc.contributor.authorScanlon, MJ
dc.date.accessioned2020-08-24T01:12:18Z
dc.date.available2020-08-24T01:12:18Z
dc.date.issued2020
dc.identifier.issn0925-2738
dc.identifier.doi10.1007/s10858-020-00339-5
dc.identifier.urihttp://hdl.handle.net/10072/396669
dc.description.abstractThe presence of suitable cavities or pockets on protein structures is a general criterion for a therapeutic target protein to be classified as 'druggable'. Many disease-related proteins that function solely through protein-protein interactions lack such pockets, making development of inhibitors by traditional small-molecule structure-based design methods much more challenging. The 22 kDa bacterial thiol oxidoreductase enzyme, DsbA, from the gram-negative bacterium Burkholderia pseudomallei (BpsDsbA) is an example of one such target. The crystal structure of oxidized BpsDsbA lacks well-defined surface pockets. BpsDsbA is required for the correct folding of numerous virulence factors in B. pseudomallei, and genetic deletion of dsbA significantly attenuates B. pseudomallei virulence in murine infection models. Therefore, BpsDsbA is potentially an attractive drug target. Herein we report the identification of a small molecule binding site adjacent to the catalytic site of oxidized BpsDsbA. 1HN CPMG relaxation dispersion NMR measurements suggest that the binding site is formed transiently through protein dynamics. Using fragment-based screening, we identified a small molecule that binds at this site with an estimated affinity of KD ~ 500 µM. This fragment inhibits BpsDsbA enzymatic activity in vitro. The binding mode of this molecule has been characterized by NMR data-driven docking using HADDOCK. These data provide a starting point towards the design of more potent small molecule inhibitors of BpsDsbA.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.relation.ispartofjournalJournal of Biomolecular NMR
dc.subject.fieldofresearchPhysical sciences
dc.subject.fieldofresearchChemical sciences
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchcode51
dc.subject.fieldofresearchcode34
dc.subject.fieldofresearchcode31
dc.subject.keywordsBpsDsbA
dc.subject.keywordsBurkholderia pseudomallei
dc.subject.keywordsCPMG relaxation dispersion
dc.subject.keywordsDisulfide oxidoreductase
dc.subject.keywordsFragment-based drug design (FBDD)
dc.titleNMR fragment screening reveals a novel small molecule binding site near the catalytic surface of the disulfide-dithiol oxidoreductase enzyme DsbA from Burkholderia pseudomallei
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationNebl, S; Alwan, WS; Williams, ML; Sharma, G; Taylor, A; Doak, BC; Wilde, KL; McMahon, RM; Halili, MA; Martin, JL; Capuano, B; Fenwick, RB; Mohanty, B; Scanlon, MJ, NMR fragment screening reveals a novel small molecule binding site near the catalytic surface of the disulfide-dithiol oxidoreductase enzyme DsbA from Burkholderia pseudomallei, Journal of Biomolecular NMR , 2020
dcterms.dateAccepted2020-07-21
dc.date.updated2020-08-24T00:08:38Z
gro.description.notepublicThis publication has been entered as an advanced online version in Griffith Research Online.
gro.hasfulltextNo Full Text
gro.griffith.authorMartin, Jennifer


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record