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

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Targeting Tenascin-C-Toll-like Receptor 4 signalling with Adhiron-derived small molecules - a viable strategy for reducing fibrosis in systemic sclerosis Thembaninkosi Gaule , Katie J. Simmons , Kieran Walker , Francesco Del Galdo , Rebecca L. Ross , Hema Viswambharan , Jahnavi Krishnappa , Jack Pacey , Martin Mcphillie , Darren C. Tomlinson , Azhar Maqbool Bioorganic Chemistry 167 DOI: 10.1016/j.bioorg.2025.109251 Open Access Show Abstract ▼ Abstract: Tissue fibrosis is a hallmark of systemic sclerosis (SSc) and results from the persistent activation of fibroblasts and excessive accumulation of extracellular matrix component such as collagen. Recent evidence implicates the matricellular protein Tenascin-C (TNC) in promoting self-sustaining fibroblast activation and fibrosis via its interaction with Toll-like receptor 4 (TLR4). In this study, we utilized Adhiron-guided ligand discovery to identify small molecule inhibitors targeting the fibrinogen-like globe domain of TNC, a key mediator of TLR4 activation. Two lead compounds (464 and 830) demonstrated structural similarity, favourable ADME profiles, and robust anti-fibrotic activity in vitro. Treatment of dermal fibroblasts derived from SSc patients with either compound significantly reduced Transforming growth factor-β-induced expression of fibrotic genes, ACTA2, COL1A1, COL1A2, and CCN2, and inhibited myofibroblast differentiation. These studies may facilitate the development of effective targeted therapy for fibrosis in SSc and support this novel strategy for small molecule development.	Dec 2025
I24-Microfocus Macromolecular Crystallography	Preclinical assessment of two FcγRI-specific antibodies that competitively inhibit immune complex-FcγRI binding to suppress autoimmune responses Tosca Holtrop , Arianne M. Brandsma , Louris J. Feitsma , Steffen Krohn , Petra Moerer , Frederique Van Den Haak , Anouk Versnel , Leonie Voss , Elsemieke M. Passchier , Maaike Nederend , J. H. Marco Jansen , Anouk G. Van Mourik , Rolf T. Urbanus , Diane Van Der Woude , Roger E. G. Schutgens , Rene E. M. Toes , Bert J. C. Janssen , Anja Lux , Kevin Budding , Matthias Peipp , Jeanette H. W. Leusen Nature Communications 16 DOI: 10.1038/s41467-025-65133-z Open Access Show Abstract ▼ Abstract: Overactivation of FcγRI by immune complexes (IC) is implicated in various autoimmune disorders and neuropathies. Currently, no effective FcγRI-specific blocking antibodies are available. Here we report preclinical data revealing two anti-FcγRI antibodies, C01 and C04, with high affinity, Fab-mediated binding within the IgG binding site on extracellular domain 2 of FcγRI. Both C01 and C04 block 90% of IgG and IC binding, and displace ~60% of pre-bound ICs without activating FcγRI, thereby minimizing the risk of aggravating inflammation. In the context of autoimmunity, C01 and C04 inhibit RA patient-derived autoantibody-IC binding to monocytes, macrophages and activated neutrophils, meanwhile they also inhibit the binding of opsonized platelets to monocytes from patients with immune thrombocytopenia. In vivo, C01 and C04 reduce IgG-dependent platelet depletion in humanized immunodeficient FcRγ-/- mice. Structural studies confirm that C01 and C04 achieve their blocking effects through Fab-mediated binding to FcγRI. Our data thus suggest that C01 and C04 may offer therapeutic potential for autoimmune disorders.	Nov 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	Phenotype-led identification of IL-10 upregulators in human CD4+ T-cells and elucidation of their pharmacology as highly selective CDK8/CDK19 inhibitors Simon Nicolle , Mike Barker , John Barrett , Matthew Campbell , Justyna Wojno-Picon , Stephen J. Atkinson , Helen Aylott , Hripsimee Kessedjian , Yanan He , Cassie Messenger , Emma Roberts , Claus Spitzfaden , Joelle Le , Nico Zinn , Thilo Werner , Birgit Dümpelfeld , Marcus Bantscheff , Don O. Somers , Heather Reid , Kevin Thang , Thomas Gobbetti , Huw D. Lewis Journal Of Medicinal Chemistry 2390 DOI: 10.1021/acs.jmedchem.4c02630 Diamond Proposal Number(s): [29352] Show Abstract ▼ Abstract: Therapeutics promoting the endogenous production of IL-10 have the potential to restore homeostasis in inflammatory disorders such as inflammatory bowel disease (IBD). Here we describe the identification of a series of IL-10 upregulators based on a pyrimidyl-piperidine scaffold through a high throughput phenotypic CD4+ T-cell multiplex assay. In vitro optimization of the initial hit yielded a lead with good potency and an in vitro clearance profile, compound 3–7, which additionally demonstrated efficacy in a murine endotoxin challenge PK–PD mechanistic model. Target deconvolution efforts identified compound 3–7 as a highly selective CDK8/19 inhibitor, and crystallographic studies unveiled its binding mode to the CDK8/Cyclin-C complex, characterized by an unusual water-mediated hydrogen bond to the kinase hinge region.	Jan 2025
I04-Macromolecular Crystallography	Design of a potent and selective dual JAK1/TYK2 inhibitor Oscar Mammoliti , Christel Menet , Céline Cottereaux , Javier Blanc , Ann De Blieck , Ghjuvanni Coti , Raphaël Geney , Line Oste , Koen Ostyn , Adeline Palisse , Evelyne Quinton , Benoit Schmitt , Monica Borgonovi , Isabelle Parent , Catherine Jagerschmidt , Steve De Vos , Béatrice Vayssiere , Miriam López-Ramos , Kenji Shoji , Reginald Brys , David Amantini , René Galien , Caroline Joannesse Bioorganic & Medicinal Chemistry 114 DOI: 10.1016/j.bmc.2024.117932 Open Access Show Abstract ▼ Abstract: Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of TH1 and TH17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model.	Nov 2024
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	HLA A24:02–restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes Garry Dolton , Anna Bulek , Aaron Wall , Hannah Thomas , Jade R. Hopkins , Cristina Rius , Sarah A. E. Galloway , Thomas Whalley , Li Rong Tan , Théo Morin , Nader Omidvar , Anna Fuller , Katie Topley , Md Samiul Hasan , Shikha Jain , Nirupa D’souza , Thomas Hodges-Hoyland , Owen B. Spiller , Deborah Kronenberg-Versteeg , Barbara Szomolay , Hugo A. Van Den Berg , Lucy C. Jones , Mark Peakman , David K. Cole , Pierre J. Rizkallah , Andrew K. Sewell Journal Of Clinical Investigation 134* DOI: 10.1172/JCI164535 Diamond Proposal Number(s): [10462, 18812] Open Access Show Abstract ▼ Abstract: CD8+ T cells destroy insulin-producing pancreatic β cells in type 1 diabetes through HLA class I–restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A24:02–peptide–TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.	Sep 2024
I03-Macromolecular Crystallography	Crystal structure of bimekizumab Fab fragment in complex with IL-17F provides molecular basis for dual IL-17A and IL-17F Inhibition Ralph Adams , Christopher G. Bunick , Alastair D. G. Lawson , Braulio Gomez , Stevan Shaw Journal Of Investigative Dermatology 11 DOI: 10.1016/j.jid.2024.03.037 Show Abstract ▼ Abstract: Psoriasis (PSO) and psoriatic arthritis (PsA) are Th17-driven inflammatory diseases where interleukin (IL)-17 cytokines like IL-17A and IL-17F promote disease pathogenesis. There are six IL-17 isoforms (IL-17A–F) and five IL-17 receptors (IL-17RA–E; Liu et al., 2020 ). IL-17 cytokines primarily function as homodimers, although IL-17A and IL-17F can heterodimerize ( Brembilla et al., 2018 ). IL-17A and IL-17F genes share the same chromosomal location (6p12), their proteins share ∼55% sequence homology, and both cytokines signal through the IL-17RA/RC heterodimeric complex ( Brembilla et al., 2018 , Liu et al., 2020 ). Inhibition of the IL-17 pathway using IL-17A targeted (secukinumab and ixekizumab) or IL-17RA targeted (brodalumab) biologics is effective in PSO and PsA. In contrast to these therapies, bimekizumab (BKZ) is a novel humanized IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A with binding affinities of 23 pM and 3.2 pM, respectively ( Adams et al., 2020 ). The clinical efficacy of BKZ warrants increased utility in patients with PSO, thereby necessitating a deeper molecular understanding of its mechanism of action ( Reich et al., 2021b , Waters et al., 2021 , Wilson et al., 2022 ).	Apr 2024
I03-Macromolecular Crystallography	Structures, functions and adaptations of the human LINE-1 ORF2 protein Eric T. Baldwin , Trevor Van Eeuwen , David Hoyos , Arthur Zalevsky , Egor P. Tchesnokov , Roberto Sánchez , Bryant D. Miller , Luciano H. Di Stefano , Francesc Xavier Ruiz , Matthew Hancock , Esin Işik , Carlos Mendez-Dorantes , Thomas Walpole , Charles Nichols , Paul Wan , Kirsi Riento , Rowan Halls-Kass , Martin Augustin , Alfred Lammens , Anja Jestel , Paula Upla , Kera Xibinaku , Samantha Congreve , Maximiliaan Hennink , Kacper B. Rogala , Anna M. Schneider , Jennifer E. Fairman , Shawn M. Christensen , Brian Desrosiers , Gregory S. Bisacchi , Oliver L. Saunders , Nafeeza Hafeez , Wenyan Miao , Rosana Kapeller , Dennis M. Zaller , Andrej Sali , Oliver Weichenrieder , Kathleen H. Burns , Matthias Götte , Michael P. Rout , Eddy Arnold , Benjamin D. Greenbaum , Donna L. Romero , John Lacava , Martin S. Taylor Nature 626, 194 - 206 DOI: 10.1038/s41586-023-06947-z Open Access Show Abstract ▼ Abstract: The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a ‘copy and paste’ mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p)1. ORF2p reverse transcriptase (RT) and endonuclease activities have been implicated in the pathophysiology of cancer2,3, autoimmunity4,5 and ageing6,7, making ORF2p a potential therapeutic target. However, a lack of structural and mechanistic knowledge has hampered efforts to rationally exploit it. We report structures of the human ORF2p ‘core’ (residues 238–1061, including the RT domain) by X-ray crystallography and cryo-electron microscopy in several conformational states. Our analyses identified two previously undescribed folded domains, extensive contacts to RNA templates and associated adaptations that contribute to unique aspects of the L1 replication cycle. Computed integrative structural models of full-length ORF2p show a dynamic closed-ring conformation that appears to open during retrotransposition. We characterize ORF2p RT inhibition and reveal its underlying structural basis. Imaging and biochemistry show that non-canonical cytosolic ORF2p RT activity can produce RNA:DNA hybrids, activating innate immune signalling through cGAS/STING and resulting in interferon production6,7,8. In contrast to retroviral RTs, L1 RT is efficiently primed by short RNAs and hairpins, which probably explains cytosolic priming. Other biochemical activities including processivity, DNA-directed polymerization, non-templated base addition and template switching together allow us to propose a revised L1 insertion model. Finally, our evolutionary analysis demonstrates structural conservation between ORF2p and other RNA- and DNA-dependent polymerases. We therefore provide key mechanistic insights into L1 polymerization and insertion, shed light on the evolutionary history of L1 and enable rational drug development targeting L1.	Feb 2024
I04-Macromolecular Crystallography	Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases Anna H. Lippert , Christopher Paluch , Meike Gaglioni , Mai T. Vuong , James Mccoll , Edward Jenkins , Martin Fellermeyer , Joseph Clarke , Sumana Sharma , Sara Moreira Da Silva , Billur Akkaya , Consuelo Anzilotti , Sara H. Morgan , Claire F. Jessup , Markus Körbel , Uzi Gileadi , Judith Leitner , Rachel Knox , Mami Chirifu , Jiandong Huo , Susan Yu , Nicole Ashman , Yuan Lui , Ian Wilkinson , Kathrine E. Attfield , Lars Fugger , Nathan J. Robertson , Christopher Lynch , Lynne Murray , Peter Steinberger , Ana Mafalda Santos , Steven F. Lee , Richard J. Cornall , David Klenerman , Simon J. Davis Immunity 57, 256 - 270.e10 DOI: 10.1016/j.immuni.2024.01.007 Diamond Proposal Number(s): [29608] Open Access Show Abstract ▼ Abstract: Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.	Feb 2024
I04-Macromolecular Crystallography	Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe Erin Bradley , Lucia Fusani , Chun-Wa Chung , Peter D. Craggs , Emmanuel H. Demont , Philip G. Humphreys , Darren J. Mitchell , Alex Phillipou , Inmaculada Rioja , Rishi R. Shah , Christopher R. Wellaway , Rab K. Prinjha , David S. Palmer , William J. Kerr , Marc Reid , Ian D. Wall , Rosa Cookson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c00906 Open Access Show Abstract ▼ Abstract: Small-molecule-mediated disruption of the protein–protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.	Nov 2023

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