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1,458 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I13-2-Diamond Manchester Imaging	Impact of therapeutic X-ray exposure on collagen I and associated proteins Ren Jie Tuieng , Catherine Disney , Sarah H. Cartmell , Cliona C. Kirwan , Alexander Eckersley , Elis Newham , Himadri S. Gupta , Judith A. Hoyland , Peter D. Lee , Michael J. Sherratt Acta Biomaterialia 10 DOI: 10.1016/j.actbio.2025.03.004 Diamond Proposal Number(s): [29784] Open Access Show Abstract ▼ Abstract: Biological tissues are exposed to X-rays in medical applications (such as diagnosis and radiotherapy) and in research studies (for example microcomputed X-ray tomography: microCT). Radiotherapy may deliver doses up to 50Gy to both tumour and healthy tissues, resulting in undesirable clinical side effects which can compromise quality of life. Whilst cellular responses to X-rays are relatively well-characterised, X-ray-induced structural damage to the extracellular matrix (ECM) is poorly understood. This study tests the hypotheses that ECM proteins and ECM-rich tissues (purified collagen I and rat tail tendons respectively) are structurally compromised by exposure to X-ray doses used in breast radiotherapy. Protein gel electrophoresis demonstrated that breast radiotherapy equivalent doses can induce fragmentation of the constituent α chains in solubilised purified collagen I. However, assembly into fibrils, either in vitro or in vivo, prevented X-ray-induced fragmentation but not structural changes (as characterised by LC-MS/MS and peptide location fingerprinting: PLF). In subsequent experiments exposure to higher (synchrotron) X-ray doses induced substantial fragmentation of solubilised and fibrillar (chicken tendon) collagen I. LC-MS/MS and PLF analysis of synchrotron-irradiated tendon identified structure-associated changes in collagens I, VI, XII, proteoglycans including aggrecan, decorin, and fibromodulin, and the elastic fibre component fibulin-1. Thus, exposure to radiotherapy X-rays can affect the structure of key tissue ECM components, although additional studies will be required to understand dose dependent effects.	Mar 2025
I03-Macromolecular Crystallography	Discovery of TNG462: a highly potent and selective MTA-cooperative PRMT5 inhibitor to target cancers with MTAP deletion Kevin M. Cottrell , Kimberly J. Briggs , Alice Tsai , Matthew R. Tonini , Douglas A. Whittington , Shanzhong Gong , Colin Liang , Patrick Mccarren , Minjie Zhang , Wenhai Zhang , Alan Huang , John P. Maxwell Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c03067 Open Access Show Abstract ▼ Abstract: The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10–15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials.	Mar 2025
Krios V-Titan Krios V at Diamond	Cryo-EM structures of apo and atorvastatin-bound human 3-hydroxy-3-methylglutaryl-coenzyme A reductase Manikandan Karuppasamy , Jason Van Rooyen Acta Crystallographica Section F Structural Biology Communications 81 DOI: 10.1107/S2053230X25001098 Diamond Proposal Number(s): [31098, 37220] Open Access Show Abstract ▼ Abstract: The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) regulates the level of cholesterol by catalysing the formation/production of mevalonate and has therefore become an important pharmaceutical target for coronary heart disease. Here, we report the cryo-EM structure of the catalytic part of the enzyme in the apo form and bound with its inhibitor atorvastatin, a commonly used drug in cardiovascular disease, at resolutions of 2.1 and 2.3 Å, respectively. In the cryo-EM maps, part of the N-domain corresponding to amino acids 439–487 is well ordered and could be modelled completely. Atorvastatin molecules were found to occupy all four active sites of the tetrameric complex, and the binding does not alter the conformation of the protein or the active site. The method described here exploits graphene oxide as an additional support and could be used as an alternative to elucidate the structures of pharmaceutical target compounds that are difficult to co-crystallize with human HMGR and for sparsely available samples in drug discovery.	Mar 2025
VMXi-Versatile Macromolecular Crystallography in situ	Human glutathione transferases catalyze the reaction between glutathione and nitrooleic acid Martina Steglich , Nicole Larrieux , Ari Zeida , Joaquín Dalla Rizza , Sonia R. Salvatore , Mariana Bonilla , Matías N. Möller , Alejandro Buschiazzo , Beatriz Alvarez , Francisco J. Schopfer , Lucía Turell Journal Of Biological Chemistry 89 DOI: 10.1016/j.jbc.2025.108362 Diamond Proposal Number(s): [33300] Open Access Show Abstract ▼ Abstract: Nitroalkene fatty acids (NO2-FAs) are formed endogenously. They regulate cell signaling pathways and are being developed clinically to treat inflammatory diseases. NO2-FAs are electrophilic and form thioether adducts with glutathione (GSH), which are exported from cells. Glutathione transferases (GSTs), a superfamily of enzymes, contribute to the cellular detoxification of hydrophobic electrophiles by catalyzing their conjugation to GSH. Herein, we evaluated the capacity of five human GSTs (M1-1, M2-2, M4-4, A4-4, and P1-1) to catalyze the reaction between nitrooleic acid (NO2-OA) and GSH. The reaction was monitored by HPLC-ESI-MS/MS and catalytic activity was detected with hGSTs M1-1 and A4-4. Using stopped-flow spectrophotometry, a 1400 and 7500-fold increase in the apparent second-order rate constant was observed for hGST M1-1 and hGST A4-4, respectively, compared to the uncatalyzed reaction (pH 7.4, 25 °C), in part due to a higher availability of the thiolate. The crystal structure of hGST M1-1 in complex with the adduct was solved at 2.55 Å resolution, revealing that the ligand was bound within the reaction center, and establishing a foundation to build a model of hGST A4-4 in complex with the adduct. A larger number of interactions between the enzyme and the fatty acid were observed for hGST A4-4 compared to hGST M1-1, probably contributing to the increased catalysis. Altogether, these results show, for the first time, that hGSTs can catalyze the reaction between GSH and NO2-FAs, likely affecting the signaling actions of these metabolites and expanding the repertoire of GST reactions.	Feb 2025
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS Avinash V. Dharmadhikari , Maria Alba Abad , Sheraz Khan , Reza Maroofian , Tristan T. Sands , Farid Ullah , Itaru Samejima , Yanwen Shen , Martin A. Wear , Kiara E. Moore , Elena Kondakova , Natalia Mitina , Theres Schaub , Grace K. Lee , Christine H. Umandap , Sara M. Berger , Alejandro D. Iglesias , Bernt Popp , Rami Abou Jamra , Heinz Gabriel , Stefan Rentas , Alyssa L. Rippert , Christopher Gray , Kosuke Izumi , Laura K. Conlin , Daniel C. Koboldt , Theresa Mihalic Mosher , Scott E. Hickey , Dara V. F. Albert , Haley Norwood , Amy Feldman Lewanda , Hongzheng Dai , Pengfei Liu , Tadahiro Mitani , Dana Marafi , Hatice Koçak Eker , Davut Pehlivan , Jennifer E. Posey , Natalie C. Lippa , Natalie Vena , Erin L. Heinzen , David B. Goldstein , Cyril Mignot , Jean-Madeleine De Sainte Agathe , Nouriya Abbas Al-Sannaa , Mina Zamani , Saeid Sadeghian , Reza Azizimalamiri , Tahere Seifia , Maha S. Zaki , Ghada M. H. Abdel-Salam , Mohamed S. Abdel-Hamid , Lama Alabdi , Fowzan Sami Alkuraya , Heba Dawoud , Aya Lofty , Peter Bauer , Giovanni Zifarelli , Erum Afzal , Faisal Zafar , Stephanie Efthymiou , Daniel Gossett , Meghan C. Towne , Raey Yeneabat , Belen Perez-Duenas , Ana Cazurro-Gutierrez , Edgard Verdura , Veronica Cantarin-Extremera , Ana Do Vale Marques , Aleksandra Helwak , David Tollervey , Sandeep N. Wontakal , Vimla S. Aggarwal , Jill A. Rosenfeld , Victor Tarabykin , Shinya Ohta , James R. Lupski , Henry Houlden , William C. Earnshaw , Erica E. Davis , A. Arockia Jeyaprakash , Jun Liao Nature Communications 16 DOI: 10.1038/s41467-025-56876-w Open Access Show Abstract ▼ Abstract: SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.	Feb 2025
I04-Macromolecular Crystallography	MTA-cooperative PRMT5 inhibitors: mechanism switching through structure-based design Kevin M. Cottrell , Douglas A. Whittington , Kimberly J. Briggs , Haris Jahic , Janid A. Ali , Alvaro J. Amor , Deepali Gotur , Matthew R. Tonini , Wenhai Zhang , Alan Huang , John P. Maxwell Journal Of Medicinal Chemistry 68, 4217 - 4236 DOI: 10.1021/acs.jmedchem.4c01998 Open Access Show Abstract ▼ Abstract: Deletion of the MTAP gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with MTAP deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target MTAP-deleted cancer cells.	Feb 2025
I04-Macromolecular Crystallography	Discovery and optimization of pyrazine carboxamide AZ3246, a selective HPK1 inhibitor Jason D. Shields , David Baker , Amber Y. S. Balazs , Gayathri Bommakanti , Robert Casella , Shenggen Cao , Steve Cook , Randolph A. Escobar , Stephen Fawell , Francis D. Gibbons , Kathryn A. Giblin , Frederick W. Goldberg , Eric Gosselin , Tyler Grebe , Niresh Hariparsad , Holia Hatoum-Mokdad , Rachel Howells , Samantha J. Hughes , Anne Jackson , Iswarya Karapa Reddy , Jason G. Kettle , Gillian M. Lamont , Scott Lamont , Min Li , Sten O. Nilsson Lill , Deanna A. Mele , Anthony J. Metrano , Adelphe M. Mfuh , Lucas A. Morrill , Bo Peng , Alexander Pflug , Theresa A. Proia , Hadi Rezaei , Ryan Richards , Magdalena Richter , Kevin J. Robbins , Maryann San Martin , Marianne Schimpl , Alwin G. Schuller , Li Sha , Minhui Shen , James E. Sheppeck , Meha Singh , Stephen Stokes , Kun Song , Yuanyuan Sun , Haoran Tang , David J. Wagner , Jianyan Wang , Yanjun Wang , David M. Wilson , Allan Wu , Chengyan Wu , Dedong Wu , Ye Wu , Kevin Xu , Yue Yang , Tieguang Yao , Minwei Ye , Andrew X. Zhang , Hui Zhang , Xiang Zhai , Yanxiao Zhou , Robert E. Ziegler , Neil P. Grimster Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c02631 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.	Feb 2025
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy Joseph A Newman , Angeline E. Gavard , Nergis Imprachim , Hazel Aitkenhead , Hadley E. Sheppard , Robert Te Poele , Paul A. Clarke , Mohammad Anwar Hossain , Louisa Temme , Hans J. Oh , Carrow I. Wells , Zachary W. Davis-Gilbert , Paul Workman , Opher Gileadi , David H. Drewry Nature Communications 16 DOI: 10.1038/s41467-025-56213-1 Diamond Proposal Number(s): [18145, 19301, 28172] Open Access Show Abstract ▼ Abstract: Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable. To investigate direct targeting of brachyury by small molecules, we determine the structure of human brachyury both alone and in complex with DNA. The structures provide insights into DNA binding and the context of the chordoma associated G177D variant. We use crystallographic fragment screening to identify hotspots on numerous pockets on the brachyury surface. Finally, we perform follow-up chemistry on fragment hits and describe the progression of a thiazole chemical series into binders with low µM potency. Thus we show that brachyury is ligandable and provide an example of how crystallographic fragment screening may be used to target protein classes that are difficult to address using other approaches.	Feb 2025
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Virtual fragment screening for DNA repair inhibitors in vast chemical space Andreas Luttens , Duc Duy Vo , Emma R. Scaletti , Elisée Wiita , Ingrid Almlöf , Olov Wallner , Jonathan Davies , Sara Kosenina , Liuzhen Meng , Maeve Long , Oliver Mortusewicz , Geoffrey Masuyer , Flavio Ballante , Maurice Michel , Evert Homan , Martin Scobie , Christina Kalderén , Ulrika Warpman Berglund , Andrii V. Tarnovskiy , Dmytro S. Radchenko , Yurii S. Moroz , Jan Kihlberg , Pål Stenmark , Thomas Helleday , Jens Carlsson Nature Communications 16 DOI: 10.1038/s41467-025-56893-9 Diamond Proposal Number(s): [21625] Open Access Show Abstract ▼ Abstract: Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 1022 compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets.	Feb 2025
B23-Circular Dichroism	Intracellular and extracellular activities of V-domain Ig-containing suppressor of T cell activation (VISTA) modulated by immunosuppressive factors of tumour microenvironment Maryam Abooali , Stephanie Schlichtner , Xi Lei , Nijas Aliu , Sabrina Ruggiero , Sonia Loges , Martin Ziegler , Franziska Hertel , Anna-Lena Volckmar , Albrecht Stenzinger , Petros Christopoulos , Michael Thomas , Elena Klenova , N. Helge Meyer , Stergios Boussios , Nigel Heaton , Yoh Zen , Ane Zamalloa , Shilpa Chokshi , Luca Urbani , Sophie Richard , Kavitha Kirubendran , Rohanah Hussain , Giuliano Siligardi , Dietmar Cholewa , Steffen M. Berger , Inna M. Yasinska , Elizaveta Fasler-Kan , Vadim V. Sumbayev Cancer Letters 41 DOI: 10.1016/j.canlet.2025.217581 Diamond Proposal Number(s): [24509, 20755, 21202] Open Access Show Abstract ▼ Abstract: V-domain Ig-containing suppressor of T cell activation (VISTA) is a unique immune checkpoint protein, which was reported to display both receptor and ligand activities. However, the mechanisms of regulation of VISTA activity and functions by factors of tumour microenvironment (TME) remain unclear and understanding these processes is required in order to develop successful personalised cancer immunotherapeutic strategies and approaches. Here we report for the very first time that VISTA interacts with another immune checkpoint protein galectin-9 inside the cell most likely facilitating its interaction with TGF-β-activated kinase 1 (TAK1). This process is required for protection of lysosomes, which is crucial for many cell types and tissues. We found that VISTA expression can be differentially controlled by crucial factors present in TME, such as transforming growth factor beta type 1 (TGF-β) and hypoxia as well as other factors activating hypoxic signalling. We confirmed that involvement of these important pathways modulated by TME differentially influences VISTA expression in different cell types. These networks include: TGF-β-Smad3 pathway, TAK1 (TGF-β-activated kinase 1) or apoptosis signal-regulating kinase 1 (ASK1)-induced activation of activating transcription factor 2 (ATF-2) and hypoxic signalling pathway. Based on this work we determined the five critical functions of VISTA and the role of TME factors in controlling (modulating or downregulating) VISTA expression.	Feb 2025

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