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26 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]

Instruments / Technical Area	Publication Details	Published
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
	The CCP 4 suite: integrative software for macromolecular crystallography Jon Agirre , Mihaela Atanasova , Haroldas Bagdonas , Charles B. Ballard , Arnaud Basle , James Beilsten-Edmands , Rafael J. Borges , David G. Brown , J. Javier Burgos-Marmol , John M. Berrisford , Paul S. Bond , Iracema Caballero , Lucrezia Catapano , Grzegorz Chojnowski , Atlanta G. Cook , Kevin D. Cowtan , Tristan I. Croll , Judit É. Debreczeni , Nicholas E. Devenish , Eleanor J. Dodson , Tarik R. Drevon , Paul Emsley , Gwyndaf Evans , Phil R. Evans , Maria Fando , James Foadi , Luis Fuentes-Montero , Elspeth F. Garman , Markus Gerstel , Richard J. Gildea , Kaushik Hatti , Maarten L. Hekkelman , Philipp Heuser , Soon Wen Hoh , Michael A. Hough , Huw T. Jenkins , Elisabet Jiménez , Robbie P. Joosten , Ronan M. Keegan , Nicholas Keep , Eugene B. Krissinel , Petr Kolenko , Oleg Kovalevskiy , Victor S. Lamzin , David M. Lawson , Andrey Lebedev , Andrew G. W. Leslie , Bernhard Lohkamp , Fei Long , Martin Maly , Airlie Mccoy , Stuart J. Mcnicholas , Ana Medina , Claudia Millán , James W. Murray , Garib N. Murshudov , Robert A. Nicholls , Martin E. M. Noble , Robert Oeffner , Navraj S. Pannu , James M. Parkhurst , Nicholas Pearce , Joana Pereira , Anastassis Perrakis , Harold R. Powell , Randy J. Read , Daniel J. Rigden , William Rochira , Massimo Sammito , Filomeno Sanchez Rodriguez , George M. Sheldrick , Kathryn L. Shelley , Felix Simkovic , Adam J. Simpkin , Pavol Skubak , Egor Sobolev , Roberto A. Steiner , Kyle Stevenson , Ivo Tews , Jens M. H. Thomas , Andrea Thorn , Josep Triviño Valls , Ville Uski , Isabel Uson , Alexei Vagin , Sameer Velankar , Melanie Vollmar , Helen Walden , David Waterman , Keith S. Wilson , Martyn Winn , Graeme Winter , Marcin Wojdyr , Keitaro Yamashita Acta Crystallographica Section D Structural Biology 79, 449 - 461 DOI: 10.1107/S2059798323003595 Open Access Show Abstract ▼ Abstract: The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.	Jun 2023
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Mapping ligand interactions of bromodomains BRD4 and ATAD2 with FragLites and PepLites - halogenated probes of druglike and peptide-like molecular interactions Gemma Davison , Mathew P. Martin , Shannon Turberville , Selma Dormen , Richard Heath , Amy B. Heptinstall , Marie Lawson , Duncan C. Miller , Yi Min Ng , James N. Sanderson , Ian Hope , Daniel Wood , Céline Cano , Jane A. Endicott , Ian R. Hardcastle , Martin E. M. Noble , Michael J. Waring Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.2c01357 Open Access Show Abstract ▼ Abstract: The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions. We extend the FragLite set with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. The output of the FragLite maps is shown to enable the development of ligands with leadlike potency. This work establishes the use of FragLite and PepLite screening at an early stage in ligand discovery allowing the rapid assessment of tractability of protein targets and informing downstream hit-finding.	Nov 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Build–couple–transform: a paradigm for lead-like library synthesis with scaffold diversity Mélanie Uguen , Gemma Davison , Lukas J. Sprenger , James H. Hunter , Mathew P. Martin , Shannon Turberville , Jessica Watt , Bernard T. Golding , Martin E. N. Noble , Hannah L. Stewart , Michael J. Waring Journal Of Medicinal Chemistry 65, 11322 - 11339 DOI: 10.1021/acs.jmedchem.2c00897 Open Access Show Abstract ▼ Abstract: High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a “build–couple–transform” paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build–couple–transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.	Aug 2022
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Parallel optimization of potency and pharmacokinetics leading to the discovery of a pyrrole carboxamide ERK5 kinase domain inhibitor Duncan C. Miller , Tristan Reuillon , Lauren Molyneux , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Ian Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , Stephanie Myers , David R. Newell , Richard A. Noble , Nicole Phillips , Laurent Rigoreau , Huw Thomas , Julie A. Tucker , Lan-Zhen Wang , Michael J. Waring , Ai-Ching Wong , Stephen R. Wedge , Martin E. M. Noble , Celine Cano Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01756 Diamond Proposal Number(s): [9948, 13587] Open Access Show Abstract ▼ Abstract: The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.	Apr 2022
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
I04-Macromolecular Crystallography	Structure-based design of potent and orally active isoindolinone inhibitors of MDM2-p53 protein–protein interaction Gianni Chessari , Ian R. Hardcastle , Jong Sook Ahn , Burcu Anil , Elizabeth Anscombe , Ruth H. Bawn , Luke D. Bevan , Timothy J. Blackburn , Ildiko Buck , Celine Cano , Benoit Carbain , Juan Castro , Ben Cons , Sarah J. Cully , Jane A. Endicott , Lynsey Fazal , Bernard T. Golding , Roger J. Griffin , Karen Haggerty , Suzannah J. Harnor , Keisha Hearn , Stephen Hobson , Rhian S. Holvey , Steven Howard , Claire E. Jennings , Christopher N. Johnson , John Lunec , Duncan C. Miller , David R. Newell , Martin E. M. Noble , Judith Reeks , Charlotte H. Revill , Christiane Riedinger , Jeffrey D. St. Denis , Emiliano Tamanini , Huw Thomas , Neil T. Thompson , Mladen Vinković , Stephen R. Wedge , Pamela A. Williams , Nicola E. Wilsher , Bian Zhang , Yan Zhao Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c02188 Show Abstract ▼ Abstract: Inhibition of murine double minute 2 (MDM2)-p53 protein–protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.	Mar 2021
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease Alice Douangamath , Daren Fearon , Paul Gehrtz , Tobias Krojer , Petra Lukacik , C. David Owen , Efrat Resnick , Claire Strain-Damerell , Anthony Aimon , Péter Ábrányi-Balogh , Jose Brandao-Neto , Anna Carbery , Gemma Davison , Alexandre Dias , Thomas D. Downes , Louise Dunnett , Michael Fairhead , James D. Firth , S. Paul Jones , Aaron Keeley , György M. Keserü , Hanna F. Klein , Mathew P. Martin , Martin M. Noble , Peter O’brien , Ailsa Powell , Rambabu N. Reddi , Rachael Skyner , Matthew Snee , Michael J. Waring , Conor Wild , Nir London , Frank Von Delft , Martin A. Walsh Nature Communications 11 DOI: 10.1038/s41467-020-18709-w Open Access Show Abstract ▼ Abstract: COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.	Oct 2020
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4 Stephanie Myers , Duncan C. Miller , Lauren Molyneux , Mercedes Arasta , Ruth H. Bawn , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Tim Hammonds , Ian R. Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , David R. Newell , Paul J. Owen , Leon C. Pang , Tristan Reuillon , Laurent J. M. Rigoreau , Huw Thomas , Julie A. Tucker , Lan-Zhen Wang , Ai-Ching Wong , Martin E. M. Noble , Stephen R. Wedge , Celine Cano European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.057 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 μM for ERK5; IC50 > 120 μM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.	May 2019
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	FragLites - minimal, halogenated fragments displaying pharmacophore doublets. An efficient approach to druggability assessment and hit generation Daniel J. Wood , José Daniel Lopez-Fernandez , Leanne E. Knight , Islam Al-Khawaldeh , Conghao Gai , Shengyin Lin , Mathew P. Martin , Duncan C. Miller , Celine Cano , Jane A. Endicott , Ian R. Hardcastle , Martin E. M. Noble , Michael J. Waring Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00304 Show Abstract ▼ Abstract: Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource intensive screening of large libraries of lead-like or fragment molecules. Here we describe an efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively and unambiguously by X-ray crystallography, exploiting the anomalous scattering of the halogen substituent. This mapping of protein interaction surfaces provides an assessment of druggability and can identify efficient start points for the de novo design of hit molecules incorporating the interacting motifs. The approach is illustrated by mapping cyclin-dependent kinase 2, which successfully identifies orthosteric and allosteric sites. The hits were rapidly elaborated to develop efficient lead-like molecules. Hence, the approach provides a new method of identifying ligand sites, assessing tractability and discovering new leads.	Mar 2019

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