dc.contributor.author | Richards, MW | |
dc.contributor.author | Burgess, SG | |
dc.contributor.author | Poon, E | |
dc.contributor.author | Carstensen, A | |
dc.contributor.author | Eilers, M | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Bayliss, R | |
dc.date.accessioned | 2017-03-24T14:24:28Z | |
dc.date.issued | 2016-11-29 | |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (48), pp. 13726 - 13731 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/498 | |
dc.identifier.eissn | 1091-6490 | |
dc.identifier.doi | 10.1073/pnas.1610626113 | |
dc.description.abstract | Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turnover by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCFFbxW7 However, N-Myc protein (the product of the MYCN oncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxW7 We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxW7 to disfavor the generation of Lys48-linked polyubiquitin chains. | |
dc.format | Print-Electronic | |
dc.format.extent | 13726 - 13731 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATL ACAD SCIENCES | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Phenylurea Compounds | |
dc.subject | Azepines | |
dc.subject | Pyrimidines | |
dc.subject | SKP Cullin F-Box Protein Ligases | |
dc.subject | Polyubiquitin | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Binding Sites | |
dc.subject | Catalytic Domain | |
dc.subject | Protein Binding | |
dc.subject | Phosphorylation | |
dc.subject | Aurora Kinase A | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.title | Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-11-29 | |
rioxxterms.versionofrecord | 10.1073/pnas.1610626113 | |
rioxxterms.licenseref.startdate | 2016-11-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Proceedings of the National Academy of Sciences of the United States of America | |
pubs.issue | 48 | |
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/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
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/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.publication-status | Published | |
pubs.volume | 113 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
dc.contributor.icrauthor | Poon, Evon | |
dc.contributor.icrauthor | Chesler, Louis | |