title: CDK1 structures reveal conserved and unique features of the essential cell cycle CDK.
abstract: CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1-Cks1 and CDK1-cyclin B-Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2-cyclin A, CDK1-cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors.
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK.
authors: Nicholas R
authors: NR
authors: Brown
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK.
authors: Svitlana
authors: S
authors: Korolchuk
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK.
authors: Mathew P
authors: MP
authors: Martin
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK.
authors: Will A
authors: WA
authors: Stanley
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK.
authors: Rouslan
authors: R
authors: Moukhametzianov
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK.|Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK.
authors: Martin E M
authors: MEM
authors: Noble
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK.|Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK.
authors: Jane A
authors: JA
authors: Endicott
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases / Q000737:chemistry* / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D002417:Cattle; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry / Q000235:genetics; D019926:Cyclin B / Q000737:chemistry* / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics; D013379:Substrate Specificity
chemical_list: C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C528899:CDK1 protein, human; C495894:CDK2 protein, human; C083689:CKS2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases