Show simple item record

dc.contributor.authorPollock, K
dc.contributor.authorLiu, M
dc.contributor.authorZaleska, M
dc.contributor.authorMeniconi, M
dc.contributor.authorPfuhl, M
dc.contributor.authorCollins, I
dc.contributor.authorGuettler, S
dc.date.accessioned2020-05-28T11:19:03Z
dc.date.issued2019-12-13
dc.identifier.citationScientific reports, 2019, 9 (1), pp. 19130 - ?
dc.identifier.issn2045-2322
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3649
dc.identifier.eissn2045-2322
dc.identifier.doi10.1101/gad.300889.117
dc.description.abstractThe PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signalling, Hippo signalling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase's poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent "scaffolding" mechanisms contribute to tankyrase function. Here we report a fragment-based screening programme against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) spectroscopy. We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
dc.formatElectronic
dc.format.extent19130 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectEscherichia coli
dc.subjectTankyrases
dc.subjectArginine
dc.subjectPeptides
dc.subjectLigands
dc.subjectFluorometry
dc.subjectMagnetic Resonance Spectroscopy
dc.subjectBinding Sites
dc.subjectCatalytic Domain
dc.subjectAnkyrin Repeat
dc.subjectProtein Binding
dc.subjectKinetics
dc.subjectMutation
dc.subjectComputer Simulation
dc.subjectWnt Signaling Pathway
dc.titleFragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.
dc.typeJournal Article
dcterms.dateAccepted2019-11-22
rioxxterms.versionofrecord10.1101/gad.300889.117
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-12-13
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScientific reports
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/In Silico Medicinal Chemistry
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/In Silico Medicinal Chemistry
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.publication-statusPublished
pubs.volume9
pubs.embargo.termsNot known
icr.researchteamIn Silico Medicinal Chemistryen_US
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamStructural Biology of Cell Signallingen_US
dc.contributor.icrauthorMeniconi, Mircoen
dc.contributor.icrauthorCollins, Ianen
dc.contributor.icrauthorGuettler, Sebastianen


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0