Jane Endicott

FragLite mapping to identify the BRD4 recruitment site of P-TEFb

Ian Hope, Richard Heath, Arnaud Baslé, Mathew P. Martin et autres

Abstract The eukaryotic positive transcription elongation factor b (P-TEFb), composed of CDK9 and cyclin T, plays a central role in regulating RNA polymerase II (RNAPII). Phosphorylation of the RNAPII C-terminal domain (CTD) by P-TEFb promotes promoter proximal pause release and enables productive …

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Diversity in CDK structural mechanisms of regulation and drug discovery opportunities

Rhianna J. Rowland, Martin E. M. Noble, Jane Endicott

Cyclin-dependent kinases (CDKs) are required for progression through the eukaryotic cell cycle and for gene transcription. The recent determination of structures of CDK-containing complexes by cryogenic electron microscopy has significantly enriched our understanding of the diverse mechanisms by which CDKs can be …

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Nanobodies restore stability to cancer-associated mutants of tumor suppressor protein p16INK4a

Owen Burbidge, Martyna W. Pastok, Diana Papini, Samantha L. Hodder et autres

We describe the generation and characterization of camelid single-domain antibodies (nanobodies) raised against tumor suppressor protein p16INK4a (p16). p16 is a cell cycle regulator that inhibits cyclin-dependent kinases CDK4 and CDK6 and is inactivated in sporadic and familial cancers. The majority of …

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Crystallographic fragment screening of CDK2-cyclin A: FragLites map sites of protein-protein interaction

Ian Hope, Mathew P. Martin, Ziwei Jiang, Michael J. Waring et autres

Sites of protein-protein interaction (PPI) are potentially more selective binding sites for therapeutics than protein substrate-binding sites. PPIs include distinct regions frequently called "hotspots," sites of key amino acid interactions. Prospective identification of these hotspots through X-ray crystallographic screening could assist in …

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Different applications and differentiated libraries for crystallographic fragment screening

Jessica E. Watt, Mathew P. Martin, Jane Endicott, Martin E. M. Noble

Macromolecular X-ray crystallography allows detection and characterisation of the binding of small, low-affinity chemical fragments. Here we review the utility of fragment screening for drug discovery, its potential for use in discovery science, as well as some of the distinct types of …

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Structural requirements for the specific binding of CRABP2 to cyclin D3

Martyna W. Pastok, Charles W.E. Tomlinson, Shannon Turberville, Abbey M. Butler et autres

Structural requirements for the specific binding of CRABP2 to cyclin D3

Martyna W. Pastok, Charles W.E. Tomlinson, Shannon Turberville, Abbey M. Butler et autres

Cellular retinoic acid binding protein 2 (CRABP2) transports retinoic acid from the cytoplasm to the nucleus where it then transfers its cargo to retinoic acid receptor-containing complexes leading to activation of gene transcription. We demonstrate using purified proteins that CRABP2 is also …

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Cryo-EM structure of the CDK2-cyclin A-CDC25A complex

Rhianna J. Rowland, Svitlana Korolchuk, Marco Salamina, Natalie J. Tatum et autres

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 …

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Crystallographic fragment screening of CDK2-cyclin A: FragLites map sites of protein-protein interaction

Ian Hope, Martin E. M. Noble, Michael J. Waring, Martin E. M. Noble et autres

Abstract Protein-protein interaction sites (PPIs) are potentially more selective therapeutic binding sites than protein substrate binding sites. PPIs include distinct regions frequently called “hotspots,” sites of key amino acid interactions. Prospective identification of these hotspots through X-ray crystallographic screening could assist in …

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Abstract 6588: Discovery of ASTX295, a potent, next-generation small molecule antagonist of MDM2 with differentiated pharmacokinetic profile

Maria Ahn, Luke Bevan, Ildiko M. Buck, Céline Cano et autres

Abstract In response to cellular stress, the tumor suppressor p53 is activated to modulate cell cycle progression, DNA repair, and apoptosis. Inhibition of the MDM2-p53 interaction in tumors carrying wild-type p53 prevents its degradation and can reactivate p53 to elicit an anti-cancer …

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Cryo-EM structure of the CDK2-cyclin A-CDC25A Complex

Rhianna J. Rowland, Svitlana Korolchuk, Marco Salamina, James R. Ault et autres

Abstract The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich motif of cyclin-dependent protein kinases (CDKs) to activate CDK activity. Here, we present the cryogenic-electron microscopy (cryo-EM) structure of CDK2-cyclin …

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Cryo-EM structure of SKP1-SKP2-CKS1 in complex with CDK2-cyclin A-p27KIP1

Rhianna J. Rowland, Richard B. Heath, Daniel P. Maskell, Rebecca F. Thompson et autres

Abstract p27KIP1 (cyclin-dependent kinase inhibitor 1B, p27) is a member of the CIP/KIP family of CDK (cyclin dependent kinase) regulators that inhibit cell cycle CDKs. p27 phosphorylation by CDK1/2, signals its recruitment to the SCFSKP2 (S-phase kinase associated protein 1 (SKP1)-cullin-SKP2) E3 …

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