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Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography	CDK1 structures reveal conserved and unique features of the essential cell cycle CDK Nicholas R. Brown , Svitlana Korolchuk , Mathew P. Martin , Will A. Stanley , Rouslan Moukhametzianov , Martin Noble , Jane A. Endicott Nature Communications 6 DOI: 10.1038/ncomms7769 PMID: 25864384 Open Access Show Abstract ▼ 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.	Nov 2015
I04-1-Macromolecular Crystallography (fixed wavelength)	Cyclin-dependent kinase (CDK) inhibitors: structure–activity relationships and insights into the CDK-2 selectivity of 6-substituted 2-arylaminopurines Christopher R Coxon , Elizabeth Anscombe , Suzannah Jane Harnor , Mathew P. Martin , Benoit Jean-Pierre Carbain , Bernard Thomas Golding , Ian Robert Hardcastle , Lisa K Harlow , Svitlana Korolchuk , Christopher J. Matheson , David R. Newell , Martin E. M. Noble , Mangaleswaran Sivaprakasam , Susan J. Tudhope , David M. Turner , Lan-Zhen Wang , Stephen R Wedge , Christopher Wong , Roger John Griffin , Jane A. Endicott , Celine Cano Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6b01254 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Purines and related heterocycles substituted at C-2 with 4’-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favour competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency towards CDK2 (IC50 0.044 μM), but was ~ 2000-fold less active towards CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket, and that is preferred in CDK2, but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.	Dec 2016
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition Daniel J. Wood , Svitlana Korolchuk , Natalie J. Tatum , Lan-Zhen Wang , Jane A. Endicott , Martin E. M. Noble , Mathew P. Martin Cell Chemical Biology DOI: 10.1016/j.chembiol.2018.10.015 Diamond Proposal Number(s): [18598, 13587] Open Access Show Abstract ▼ Abstract: Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.	Nov 2018
B21-High Throughput SAXS I04-1-Macromolecular Crystallography (fixed wavelength)	Discriminative SKP2 interactions with CDK-cyclin complexes support a cyclin a-specific role in p27KIP1 degradation Marco Salamina , Bailey C. Montefiore , Mengxi Liu , Daniel J. Wood , Richard Heath , James R. Ault , Lan-Zhen Wang , Svitlana Korolchuk , Arnaud Basle , Martyna Pastok , Judith Reeks , Natalie J. Tatum , Frank Sobott , Stefan T. Arold , Michele Pagano , Martin E. M. Noble , Jane A. Endicott Journal Of Molecular Biology 433 DOI: 10.1016/j.jmb.2020.166795 Diamond Proposal Number(s): [13587, 16970] Open Access Show Abstract ▼ Abstract: The SCFSKP2 ubiquitin ligase relieves G1 checkpoint control of CDK-cyclin complexes by promoting p27KIP1 degradation. We describe reconstitution of stable complexes containing SKP1-SKP2 and CDK1-cyclin B or CDK2-cyclin A/E, mediated by the CDK regulatory subunit CKS1. We further show that a direct interaction between a SKP2 N-terminal motif and cyclin A can stabilize SKP1-SKP2-CDK2-cyclin A complexes in the absence of CKS1. We identify the SKP2 binding site on cyclin A and demonstrate the site is not present in cyclin B or cyclin E. This site is distinct from but overlapping with features that mediate binding of p27KIP1 and other G1 cyclin regulators to cyclin A. We propose that the capacity of SKP2 to engage with CDK2-cyclin A by more than one structural mechanism provides a way to fine tune the degradation of p27KIP1 and distinguishes cyclin A from other G1 cyclins to ensure orderly cell cycle progression.	Mar 2021
Krios I-Titan Krios I at Diamond	Cryo-EM structure of the CDK2-cyclin A-CDC25A complex Rhianna J. Rowland , Svitlana Korolchuk , Marco Salamina , Natalie J. Tatum , James R. Ault , Sam Hart , Johan P. Turkenburg , James N. Blaza , Martin E. M. Noble , Jane A. Endicott Nature Communications 15 DOI: 10.1038/s41467-024-51135-w Diamond Proposal Number(s): [28576] Open Access Show Abstract ▼ Abstract: The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present the cryo-EM structure of CDK2-cyclin A in complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further identify a CDC25A C-terminal helix that is critical for complex formation. Sequence conservation analysis suggests CDK1/2-cyclin A, CDK1-cyclin B and CDK2/3-cyclin E are suitable binding partners for CDC25A, whilst CDK4/6-cyclin D complexes appear unlikely substrates. A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.	Aug 2024

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