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dc.contributor.authorGreber, BJ
dc.contributor.authorPerez-Bertoldi, JM
dc.contributor.authorLim, K
dc.contributor.authorIavarone, AT
dc.contributor.authorToso, DB
dc.contributor.authorNogales, E
dc.date.accessioned2020-09-16T13:07:37Z
dc.date.issued2020-09
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2020, 117 (37), pp. 22849 - 22857
dc.identifier.issn0027-8424
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4067
dc.identifier.eissn1091-6490
dc.identifier.doi10.1073/pnas.2009627117
dc.description.abstractThe human CDK-activating kinase (CAK), a complex composed of cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the C-terminal heptapeptide repeat domain of the RNA polymerase II (Pol II) subunit RPB1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell cycle progression. Here, we have determined the three-dimensional (3D) structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and to aid in the rational design of therapeutic compounds.
dc.formatPrint-Electronic
dc.format.extent22849 - 22857
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.subjectHumans
dc.subjectRNA Polymerase II
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectCyclin-Dependent Kinases
dc.subjectTranscription Factors
dc.subjectCryoelectron Microscopy
dc.subjectCell Cycle
dc.subjectCell Division
dc.subjectPhosphorylation
dc.titleThe cryoelectron microscopy structure of the human CDK-activating kinase.
dc.typeJournal Article
rioxxterms.versionofrecord10.1073/pnas.2009627117
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2020-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfProceedings of the National Academy of Sciences of the United States of America
pubs.issue37
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume117
pubs.embargo.termsNo embargo
dc.contributor.icrauthorGreber, Basilen


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