dc.contributor.author | Pollock, K | |
dc.contributor.author | Liu, M | |
dc.contributor.author | Zaleska, M | |
dc.contributor.author | Meniconi, M | |
dc.contributor.author | Pfuhl, M | |
dc.contributor.author | Collins, I | |
dc.contributor.author | Guettler, S | |
dc.date.accessioned | 2020-05-28T11:19:03Z | |
dc.date.issued | 2019-12-13 | |
dc.identifier.citation | Scientific reports, 2019, 9 (1), pp. 19130 - ? | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3649 | |
dc.identifier.eissn | 2045-2322 | |
dc.identifier.doi | 10.1101/gad.300889.117 | |
dc.description.abstract | The 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.format | Electronic | |
dc.format.extent | 19130 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Escherichia coli | |
dc.subject | Tankyrases | |
dc.subject | Arginine | |
dc.subject | Peptides | |
dc.subject | Ligands | |
dc.subject | Fluorometry | |
dc.subject | Magnetic Resonance Spectroscopy | |
dc.subject | Binding Sites | |
dc.subject | Catalytic Domain | |
dc.subject | Ankyrin Repeat | |
dc.subject | Protein Binding | |
dc.subject | Kinetics | |
dc.subject | Mutation | |
dc.subject | Computer Simulation | |
dc.subject | Wnt Signaling Pathway | |
dc.title | Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-11-22 | |
rioxxterms.versionofrecord | 10.1101/gad.300889.117 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-12-13 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Scientific reports | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 9 | |
pubs.embargo.terms | Not known | |
icr.researchteam | In Silico Medicinal Chemistry | |
icr.researchteam | Medicinal Chemistry 2 | |
icr.researchteam | Structural Biology of Cell Signalling | |
dc.contributor.icrauthor | Meniconi, Mirco | |
dc.contributor.icrauthor | Collins, Ian | |
dc.contributor.icrauthor | Guettler, Sebastian | |