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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1 Emily C. Hank , Nicholas D. D'Arcy-Evans , Emma R. Scaletti , Carlos Benítez-Buelga , Olov Wallner , Florian Ortis , Kaixin Zhou , Liuzhen Meng , Alicia Del Prado , Patricia Calvo , Ingrid Almlöf , Elisée Wiita , Karen Nierlin , Sara Kosenina , Andreas Krämer , Alice Eddershaw , Mario Kehler , Maeve Long , Ann-Sofie Jemth , Holly Dawson , Josephine Stewart , Adam Dickey , Mikhael E. Astorga , Marek Varga , Evert J. Homan , Martin Scobie , Stefan Knapp , Leandro Sastre , Pal Stenmark , Miguel De Vega , Thomas Helleday , Maurice Michel Rsc Chemical Biology DOI: 10.1039/D4CB00323C Diamond Proposal Number(s): [15806, 21625] Open Access Show Abstract ▼ Abstract: Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with an abasic (AP) site base excision repair intermediate. For 8-oxoguanine DNA glycosylase 1 (OGG1), cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair in DNA. Evolution has led OGG1 to use a product-assisted catalysis approach, where the excised 8-oxoG acts as a Brønsted base for cleavage of a Schiff base intermediate. However, the physicochemical properties of 8-oxoG significantly limit the inherent enzymatic turnover leading to a weak, cellularly absent, AP lyase activity. We hypothesized that chemical synthesis of purine analogues enables access to complex structures that are suitable as product-like catalysts. Herein, the nucleobase landscape is profiled for its potential to increase OGG1 Schiff base cleavage. 8-Substituted 6-thioguanines emerge as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination. This effectively broadens the enzymatic substrate scope of OGG1, shaping a complete, artificial AP-lyase function. In addition, a second class of compounds, 6-substituted pyrazolo-[3,4-d]-pyrimidines, stimulate OGG1 function at high pH, while thioguanines govern enzymatic control at acidic pH. This enables up to 20-fold increased enzyme turnover and a de novo OGG1 β-elimination in conditions commonly not tolerated. The tool compounds employed here are non-toxic in cells and stimulate the repair of AP sites through a natural, APE1 dependent pathway, as opposed to previously reported β,δ-lyase stimulator TH10785.	Oct 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
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Optimization of N-piperidinyl-benzimidazolone derivatives as potent and selective inhibitors of 8-oxo guanine DNA glycosylase 1 Olov Wallner , Armando Cázares-Körner , Emma R. Scaletti , Geoffrey Masuyer , Tove Bekkhus , Torkild Visnes , Kirill Mamonov , Florian Ortis , Thomas Lundbäck , Maria Volkova , Tobias Koolmeister , Elisée Wiita , Olga Loseva , Monica Pandey , Evert Homan , Carlos Benítez-Buelga , Jonathan Davies , Martin Scobie , Ulrika Warpman Berglund , Christina Kalderén , Pal Stenmark , Thomas Helleday , Maurice Michel Chemmedchem DOI: 10.1002/cmdc.202200310 Diamond Proposal Number(s): [15806, 21625] Open Access Show Abstract ▼ Abstract: 8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G:C→T:A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N -piperidinyl-benzimidazolones. Using X-ray crystallography data, we describe the surprising binding mode of different members of the class. Potent members adopt a chair within the N -Piperidinyl-linker, while a boat conformation was found for weaker analogues.	Sep 2022
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function Maurice Michel , Carlos Benítez-Buelga , Patricia A. Calvo , Bishoy M. F. Hanna , Oliver Mortusewicz , Geoffrey Masuyer , Jonathan Davies , Olov Wallner , Sanjiv Kumar , Julian J. Albers , Sergio Castañeda-Zegarra , Ann-Sofie Jemth , Torkild Visnes , Ana Sastre-Perona , Akhilesh N. Danda , Evert J. Homan , Karthick Marimuthu , Zhao Zhenjun , Celestine N. Chi , Antonio Sarno , Elisée Wiita , Catharina Von Nicolai , Anna J. Komor , Varshni Rajagopal , Sarah Müller , Emily C. Hank , Marek Varga , Emma R. Scaletti , Monica Pandey , Stella Karsten , Hanne Haslene-Hox , Simon Loevenich , Petra Marttila , Azita Rasti , Kirill Mamonov , Florian Ortis , Fritz Schömberg , Olga Loseva , Josephine Stewart , Nicholas D’arcy-Evans , Tobias Koolmeister , Martin Henriksson , Dana Michel , Ana De Ory , Lucia Acero , Oriol Calvete , Martin Scobie , Christian Hertweck , Ivan Vilotijevic , Christina Kalderén , Ana Osorio , Rosario Perona , Alexandra Stolz , Pal Stenmark , Ulrika Warpman Berglund , Miguel De Vega , Thomas Helleday Science 376, 1471 - 1476 DOI: 10.1126/science.abf8980 Diamond Proposal Number(s): [15806, 21625] Show Abstract ▼ Abstract: Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.	Jun 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress Nadilly Bonagas , Nina M. S. Gustafsson , Martin Henriksson , Petra Marttila , Robert Gustafsson , Elisée Wiita , Sanjay Borhade , Alanna C. Green , Karl S. A. Vallin , Antonio Sarno , Richard Svensson , Camilla Göktürk , Therese Pham , Ann-Sofie Jemth , Olga Loseva , Victoria Cookson , Nicole Kiweler , Lars Sandberg , Azita Rasti , Judith E. Unterlass , Martin Haraldsson , Yasmin Andersson , Emma R. Scaletti , Christoffer Bengtsson , Cynthia B. J. Paulin , Kumar Sanjiv , Eldar Abdurakhmanov , Linda Pudelko , Ben Kunz , Matthieu Desroses , Petar Iliev , Katarina Färnegårdh , Andreas Krämer , Neeraj Garg , Maurice Michel , Sara Häggblad , Malin Jarvius , Christina Kalderén , Amanda Bögedahl Jensen , Ingrid Almlöf , Stella Karsten , Si Min Zhang , Maria Häggblad , Anders Eriksson , Jianping Liu , Björn Glinghammar , Natalia Nekhotiaeva , Fredrik Klingegård , Tobias Koolmeister , Ulf Martens , Sabin Llona-Minguez , Ruth Moulson , Helena Nordström , Vendela Parrow , Leif Dahllund , Birger Sjöberg , Irene L. Vargas , Duy Duc Vo , Johan Wannberg , Stefan Knapp , Hans E. Krokan , Per I. Arvidsson , Martin Scobie , Johannes Meiser , Pal Stenmark , Ulrika Warpman Berglund , Evert J. Homan , Thomas Helleday Nature Cancer 3, 156 - 172 DOI: 10.1038/s43018-022-00331-y Open Access Show Abstract ▼ Abstract: The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.	Feb 2022
	Target 2035 – update on the quest for a probe for every protein Susanne Müller , Suzanne Ackloo , Arij Al Chawaf , Bissan Al-Lazikani , Albert Antolin , Jonathan B. Baell , Hartmut Beck , Shaunna Beedie , Ulrich A. K. Betz , Gustavo Arruda Bezerra , Paul E. Brennan , David Brown , Peter J. Brown , Alex N. Bullock , Adrian J. Carter , Apirat Chaikuad , Mathilde Chaineau , Alessio Ciulli , Ian Collins , Jan Dreher , David Drewry , Kristina Edfeldt , Aled M. Edwards , Ursula Egner , Stephen V. Frye , Stephen M. Fuchs , Matthew D. Hall , Ingo V. Hartung , Alexander Hillisch , Stephen H. Hitchcock , Evert Homan , Natarajan Kannan , James R. Kiefer , Stefan Knapp , Milka Kostic , Stefan Kubicek , Andrew S. Leach , Sven Lindemann , Brian D. Marsden , Hisanori Matsui , Jordan L. Meier , Daniel Merk , Maurice Michel , Maxwell R. Morgan , Anke Mueller-Fahrnow , Dafydd R. Owen , Benjamin G. Perry , Saul H. Rosenberg , Kumar Singh Saikatendu , Matthieu Schapira , Cora Scholten , Sujata Sharma , Anton Simeonov , Michael Sundström , Giulio Superti-Furga , Matthew H. Todd , Claudia Tredup , Masoud Vedadi , Frank Von Delft , Timothy M. Willson , Georg E. Winter , Paul Workman , Cheryl H. Arrowsmith Rsc Medicinal Chemistry 17 DOI: 10.1039/D1MD00228G Open Access Show Abstract ▼ Abstract: Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.	Dec 2021
I24-Microfocus Macromolecular Crystallography	Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity Daniel Rehling , Si Min Zhang , Ann-Sofie Jemth , Tobias Koolmeister , Adam Throup , Olov Wallner , Emma Scaletti , Takaya Moriyama , Rina Nishii , Jonathan Davies , Matthieu Desroses , Sean G. Rudd , Martin Scobie , Evert Homan , Ulrika Warpman Berglund , Jun J. Yang , Thomas Helleday , Pal Stenmark Journal Of Biological Chemistry 271 DOI: 10.1016/j.jbc.2021.100568 Diamond Proposal Number(s): [21625] Open Access Show Abstract ▼ Abstract: The enzyme NUDT15 efficiently hydrolyses the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and pre-emptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants due to their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared to TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.	Mar 2021
I04-Macromolecular Crystallography	Targeting OGG1 arrests cancer cell proliferation by inducing replication stress Torkild Visnes , Carlos Benítez-Buelga , Armando Cázares-Körner , Kumar Sanjiv , Bishoy M. F. Hanna , Oliver Mortusewicz , Varshni Rajagopal , Julian J. Albers , Daniel W Hagey , Tove Bekkhus , Saeed Eshtad , Juan Miguel Baquero , Geoffrey Masuyer , Olov Wallner , Sarah Müller , Therese Pham , Camilla Göktürk , Azita Rasti , Sharda Suman , Raúl Torres-Ruiz , Antonio Sarno , Elisée Wiita , Evert J. Homan , Stella Karsten , Karthick Marimuthu , Maurice Michel , Tobias Koolmeister , Martin Scobie , Olga Loseva , Ingrid Almlöf , Judith Edda Unterlass , Aleksandra Pettke , Johan Boström , Monica Pandey , Helge Gad , Patrick Herr , Ann-Sofie Jemth , Samir El andaloussi , Christina Kalderén , Sandra Rodriguez-Perales , Javier Benítez , Hans E Krokan , Mikael Altun , Pal Stenmark , Ulrika Warpman Berglund , Thomas Helleday Nucleic Acids Research 434 DOI: 10.1093/nar/gkaa1048 Diamond Proposal Number(s): [15806] Open Access Show Abstract ▼ Abstract: Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.	Nov 2020
I24-Microfocus Macromolecular Crystallography	Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target Jana Skerlova , Judith Unterlass , Mona Göttmann , Petra Marttila , Evert Homan , Thomas Helleday , Ann-Sofie Jemth , Pal Stenmark Journal Of Biological Chemistry DOI: 10.1074/jbc.RA120.013695 Diamond Proposal Number(s): [15806] Open Access Show Abstract ▼ Abstract: The bifunctional human enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) catalyzes two essential steps in the de novo purine biosynthesis pathway. PAICS is overexpressed in many cancers and could be a promising target for the development of cancer therapeutics. Here, using gene knockdowns and clonogenic survival and cell viability assays, we demonstrate that PAICS is required for growth and survival of prostate cancer cells. PAICS catalyzes the carboxylation of aminoimidazole ribonucleotide (AIR) and the subsequent conversion of carboxyaminoimidazole ribonucleotide (CAIR) and L-aspartate to N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR). Of note, we present the first structures of human octameric PAICS in complexes with native ligands. In particular, we report the structure of PAICS with CAIR bound in the active sites of both domains and SAICAR bound in one of the SAICAR synthetase domains. Moreover, we report the PAICS structure with SAICAR and an ATP analog occupying the SAICAR synthetase active site. These structures provide insight into substrate and product binding and the architecture of the active sites, disclosing important structural information for rational design of PAICS inhibitors as potential anticancer drugs.	Jun 2020
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation Torkild Visnes , Armando Cázares-Körner , Wenjing Hao , Olov Wallner , Geoffrey Masuyer , Olga Loseva , Oliver Mortusewicz , Elisée Wiita , Antonio Sarno , Aleksandr Manoilov , Juan Astorga-Wells , Ann-Sofie Jemth , Lang Pan , Kumar Sanjiv , Stella Karsten , Camilla Gokturk , Maurice Grube , Evert J. Homan , Bishoy M. F. Hanna , Cynthia B. J. Paulin , Therese Pham , Azita Rasti , Ulrika Warpman Berglund , Catharina Von Nicolai , Carlos Benitez-Buelga , Tobias Koolmeister , Dag Ivanic , Petar Iliev , Martin Scobie , Hans E. Krokan , Pawel Baranczewski , Per Artursson , Mikael Altun , Annika Jenmalm Jensen , Christina Kalderén , Xueqing Ba , Roman A. Zubarev , Pal Stenmark , Istvan Boldogh , Thomas Helleday Science 362, 834 - 839 DOI: 10.1126/science.aar8048 Diamond Proposal Number(s): [15806] Show Abstract ▼ Abstract: The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.	Nov 2018

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