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

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Targeted protein degradation of NUDT5 dissociates catalytic inhibition from protein loss in 6-thioguanine response Anne-Sophie M. C. Marques , Ludwig G. Bauer , Tuan-Anh Nguyen , Alejandro Gonzalez Orta , Jan-Lennart Venne , Carol Cheng , Esra Balikci , Yusi Liu , Barr Tivon , Alena Kroupova , Alessio Ciulli , Nir London , Stefan Kubicek , Kilian V. M. Huber Nature Communications DOI: 10.1038/s41467-026-74489-9 Open Access Show Abstract ▼ Abstract: 6-Thioguanine (6-TG) is an FDA-approved antimetabolite drug that is widely used clinically, including for the treatment of leukemia. Its cellular effects require metabolic activation and are regulated through interactions with various proteins such as NUDT15, which catalyzes the hydrolysis of the active 6-TG metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP. Recent genome-wide CRISPR loss-of-function studies have identified another NUDIX hydrolase, NUDT5, as a crucial mediator of 6-TG toxicity. Here, we develop and validate a selective, cell-active NUDT5 degrader toolkit and orthogonally characterize target engagement, ternary complex formation, degradation kinetics, and proteome-wide selectivity. These degraders, in conjunction with orthogonal CRISPR knock-out and reconstitution experiments, support a non-enzymatic role for NUDT5 in modulating the cellular response to 6-TG. Depletion of NUDT5 protein is antagonistic to NUDT15 inhibition, suggesting a distinct mode-of-action with potential implications for patient therapy.	Jun 2026
I24-Microfocus Macromolecular Crystallography	BromoCatch: a self-labelling tag platform for protein modification and live cell imaging Maria Rodriguez-Rios , Conner Craigon , Mark A. Nakasone , Gajanan Sathe , Adam G. Bond , Mark Dorward , Anthony K. Edmonds , Mark C. Norley , Robert E. Arnold , Paul M. Wood , Stephen J. Reynolds , Joel Cresser-Brown , Graham P. Marsh , Hannah J. Maple , Alessio Ciulli Nature Communications DOI: 10.1038/s41467-026-72539-w Diamond Proposal Number(s): [35324] Open Access Show Abstract ▼ Abstract: Visualizing and manipulating proteins in live cells is crucial for studying complex biological processes. Self-labelling protein (SLP) tags such as HaloTag and SNAP-tag are widely used for protein labelling, and new systems are needed to expand multiplexing capabilities and broaden the scope of applications. Here we present BromoCatch, a small ~13 kDa bromodomain (BD)-based SLP platform, engineered with a nucleophilic cysteine for covalent ligand engagement. A structure-based designed library of electrophilic ligands was screened against two cysteine-containing mutants using differential scanning fluorimetry and intact protein mass spectrometry to assess covalent complex formation. We identified a para-acrylamide bumped derivative MR116 and the Brd4-BD2 double mutant L387A,E438C as the optimal protein-ligand pair, and reveal the binding mode through an X-ray co-crystal structure solved to 1.3 Å resolution. BromoCatch demonstrated potent and irreversible cellular target engagement in NanoBRET and residence-time assays. Its versatility was demonstrated through the design of a biotinylated conjugate, PROTAC-based degraders, and fluorescent full-on and “switch-on” probes for ex-cellulo and live-cell imaging, including side-by-side comparison and orthogonality with HaloTag. Together, these results establish BromoCatch as a robust, modular, and orthogonal SLP tool with broad potential for multiplexed labelling and targeted protein manipulation.	May 2026
Krios II-Titan Krios II at Diamond	Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation Valentina A. Spiteri , Dmitri Segal , Alejandro Correa-Sáez , Kentaro Iso , Ryan Casement , Miquel Muñoz I Ordoño , Mark A. Nakasone , Gajanan Sathe , Caroline Schätz , Hannah E. Peters , Mark Doward , Lisa Kainacher , Angus D. Cowan , Alessio Ciulli , Georg E. Winter Nature Chemical Biology 21 DOI: 10.1038/s41589-026-02224-y Diamond Proposal Number(s): [37630] Open Access Show Abstract ▼ Abstract: Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) target proteins for degradation by co-opting an E3 ligase. While heterotrivalent PROTACs that can recruit multiple E3 ligases have been described, all MGDs reported to date depend on a single E3. Using orthogonal genetic screening, biophysical and structural analyses, we show that a monovalent MGD can recruit CUL4DCAF16 and CRL1FBXO22 in parallel to degrade SMARCA2/4. Deep mutational scanning identifies C173 in DCAF16 as essential for degrader activity and intact protein mass spectrometry confirms covalent modification at this site. Elucidating the ternary complex structure reveals a unique binding mode and a distinct interface of neointeractions that underlie degrader specificity. We demonstrate that ligase dependency is chemically and genetically tunable. Minimal compound modifications shift preference from DCAF16 to FBXO22, while a single substitution boosts degrader dependency on DCAF16. These results establish a framework for designing tunable dual E3 ligase degraders to mitigate potential resistance mechanisms.	May 2026
I24-Microfocus Macromolecular Crystallography	High-throughput ligand diversification to discover chemical inducers of proximity James B. Shaum , Miquel Muñoz I Ordoño , Erica A. Steen , Daniela V. Wenge , Hakyung Cheong , Jordan Janowski , Moritz Hunkeler , Eric M. Bilotta , Zoe J. Rutter , Paige A. Barta , Abby M. Thornhill , Natalia Milosevich , Lauren M. Hargis , Timothy R. Bishop , Trever R. Carter , Bryce Da Camara , Matthias Hinterndorfer , Lucas Dada , Wen-Ji He , Fabian Offensperger , Hirotake Furihata , Sydney R. Schweber , Charlie Hatton , Yanhe Wen , Benjamin F. Cravatt , Keary M. Engle , Katherine A. Donovan , Bruno Melillo , Seiya Kitamura , Alessio Ciulli , Scott A. Armstrong , Eric S. Fischer , Georg E. Winter , Michael A. Erb Nature Chemical Biology 184 DOI: 10.1038/s41589-025-02137-2 Diamond Proposal Number(s): [35324] Open Access Show Abstract ▼ Abstract: Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While the discovery of heterobifunctional CIPs is expedited by rational design strategies, molecular glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein–ligand interface. Using sulfur(VI) fluoride exchange-based high-throughput chemistry (HTC) to install 3,163 structurally diverse building blocks onto ENL (eleven-nineteen leukemia) and BRD4 (bromodomain-containing protein 4) ligands, we screened each analog for degrader activity. This revealed dHTC1, an ENL degrader that recruits CRL4CRBN complex through an extended interface of protein–protein contacts and only engages CRBN after pre-forming the ENL:dHTC1 complex. We also identified dHTC3, a molecular glue that selectively dimerizes BRD4 bromodomain 1 to SCFFBXO3, an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and new effectors for proximity pharmacology.	Feb 2026
I24-Microfocus Macromolecular Crystallography	Identification of a highly cooperative PROTAC degrader targeting GTP-loaded KRAS(On) alleles Alessio Ciulli , Peter Ettmayer , Kirsten Mcaulay , Vesna Vetma , Ilaria Puoti , Natalia Karolak , Sohini Chakraborti , Emelyne Diers , Enrico Girardi , Shakil Khan , Giorgia Kidd , Katrin G. Kropatsch , Ross Mclennan , Suzanne O’connor , Matthias Samwer , Nicole Trainor , Claire Whitworth , Andre J. Wijaya , Jeff Y. F. Wong , David Zollman , William Farnaby , Johannes Popow Journal Of The American Chemical Society DOI: 10.1021/jacs.5c10354 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequently mutated oncogene in multiple types of cancer and is a high priority target for oncology drug development. There are many different KRAS mutations, including mutations that favor the GTP-loaded hydrolysis-incompetent “active” state of KRAS, KRAS(on), that can lead to tumorigenesis. However, small molecule interventions thus far have predominantly targeted single mutations of “inactive” GDP-loaded KRAS, KRAS(off), such as KRASG12C. Here, we address this gap through the development of heterobifunctional VHL-based PROTACs capable of engaging and degrading KRAS(on), thus addressing a wider range of KRAS mutations. By studying ternary complex affinity, stability, and binding modes using SPR and X-ray cocrystal structures, we identified PROTACs that exhibit high positive cooperativity in forming ternary complexes with VHL and GCP-loaded KRAS as representative of KRAS(on) variants. Degrader activity profiling in relevant cancer cells supported the discovery of ACBI4, a PROTAC which forms a highly stable and cooperative ternary complex between VHL and GTP-bound KRAS and which potently degrades KRASG12R, leading to antiproliferative effect in KRAS mutant-driven cancer cells. ACBI4 provides a new chemical tool for studying the impact of degrading KRAS(on) mutants, which is not possible with current pan-KRAS inhibitors or degraders.	Oct 2025
I24-Microfocus Macromolecular Crystallography	Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes Ning Ma , Supriyo Bhattacharya , Sanychen Muk , Zuzana Jandova , Philipp S. Schmalhorst , Soumadwip Ghosh , Keith Le , Emelyne Diers , Nicole Trainor , William Farnaby , Michael J. Roy , Christiane Kofink , Peter Greb , Harald Weinstabl , Alessio Ciulli , Gerd Bader , Kyra Sankar , Andreas Bergner , Nagarajan Vaidehi Nature Communications 16 DOI: 10.1038/s41467-025-63713-7 Open Access Show Abstract ▼ Abstract: Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2–VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or ‘frustrated,’ configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design.	Sep 2025
	Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open Claudia Tredup , Suzanne Ackloo , Hartmut Beck , Peter J. Brown , Alex N. Bullock , Alessio Ciulli , Ivan Dikic , Kristina Edfeldt , Aled M. Edwards , Jonathan M. Elkins , Henner F. Farin , Edward A. Fon , Matthias Gstaiger , Judith Günther , Anna-Lena Gustavsson , Sandra Häberle , Laura Isigkeit , Kilian V. M. Huber , Andras Kotschy , Oliver Krämer , Andrew R. Leach , Brian D. Marsden , Hisanori Matsui , Daniel Merk , Florian Montel , Monique P. C. Mulder , Susanne Müller , Dafydd R. Owen , Ewgenij Proschak , Sandra Röhm , Alexandra Stolz , Michael Sundström , Frank Von Delft , Timothy M. Willson , Cheryl H. Arrowsmith , Stefan Knapp Rsc Medicinal Chemistry 11 DOI: 10.1039/D4MD00735B Open Access Show Abstract ▼ Abstract: Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public–private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.	Nov 2024
B21-High Throughput SAXS I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders Alena Kroupova , Valentina A. Spiteri , Zoe J. Rutter , Hirotake Furihata , Darren Darren , Sarath Ramachandran , Sohini Chakraborti , Kevin Haubrich , Julie Pethe , Denzel Gonzales , Andre J. Wijaya , Maria Rodriguez-Rios , Manon Sturbaut , Dylan M. Lynch , William Farnaby , Mark A. Nakasone , David Zollman , Alessio Ciulli Nature Communications 15 DOI: 10.1038/s41467-024-52871-9 Diamond Proposal Number(s): [26793, 35324, 33832, 38813] Open Access Show Abstract ▼ Abstract: The ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide and is recruited by most targeted protein degraders (PROTACs and molecular glues) in clinical development. Biophysical and structural investigation of CRBN has been limited by current constructs that either require co-expression with the adaptor DDB1 or inadequately represent full-length protein, with high-resolution structures of degrader ternary complexes remaining rare. We present the design of CRBNmidi, a construct that readily expresses from E. coli with high yields as soluble, stable protein without DDB1. We benchmark CRBNmidi for wild-type functionality through a suite of biophysical techniques and solve high-resolution co-crystal structures of its binary and ternary complexes with degraders. We qualify CRBNmidi as an enabling tool to accelerate structure-based discovery of the next generation of CRBN based therapeutics.	Oct 2024
Krios I-Titan Krios I at Diamond	Mechanism of degrader-targeted protein ubiquitinability Charlotte Crowe , Mark A. Nakasone , Sarah Chandler , Conner Craigon , Gajanan Sathe , Michael H. Tatham , Nikolai Makukhin , Ronald T. Hay , Alessio Ciulli Science Advances 10 DOI: 10.1126/sciadv.ado6492 Diamond Proposal Number(s): [31827] Open Access Show Abstract ▼ Abstract: Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4BD2 toward UBE2R1-ubiquitin, and Lys456 at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4BD2, with cellular degradation and ubiquitinomics confirming the importance of Lys456 and nearby Lys368/Lys445, identifying the “ubiquitination zone.” Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4BD2 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.	Oct 2024
I24-Microfocus Macromolecular Crystallography	Targeting cancer with small-molecule pan-KRAS degraders Johannes Popow , William Farnaby , Andreas Gollner , Christiane Kofink , Gerhard Fischer , Melanie Wurm , David Zollman , Andre Wijaya , Nikolai Mischerikow , Carina Hasenoehrl , Polina Prokofeva , Heribert Arnhof , Silvia Arce-Solano , Sammy Bell , Georg Boeck , Emelyne Diers , Aileen B. Frost , Jake Goodwin-Tindall , Jale Karolyi-Oezguer , Shakil Khan , Theresa Klawatsch , Manfred Koegl , Roland Kousek , Barbara Kratochvil , Katrin Kropatsch , Arnel A. Lauber , Ross Mclennan , Sabine Olt , Daniel Peter , Oliver Petermann , Vanessa Roessler , Peggy Stolt-Bergner , Patrick Strack , Eva Strauss , Nicole Trainor , Vesna Vetma , Claire Whitworth , Siying Zhong , Jens Quant , Harald Weinstabl , Bernhard Kuster , Peter Ettmayer , Alessio Ciulli Science 385, 1338 - 1347 DOI: 10.1126/science.adm8684 Diamond Proposal Number(s): [14980] Show Abstract ▼ Abstract: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.	Sep 2024

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