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732 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
B21-High Throughput SAXS	Exploring Calbindin-IMPase fusion proteins structure and activity James Noble , John R. Atack Biochemistry And Biophysics Reports 30 DOI: 10.1016/j.bbrep.2022.101266 Diamond Proposal Number(s): [14891] Open Access Show Abstract ▼ Abstract: Calbindin-D28k is a calcium binding protein that is highly expressed in the mammalian central nervous system. It has been reported that calbindin-D28k binds to and increases the activity of inositol Monophosphatase (IMPase). This is an enzyme that is involved in the homeostasis of the Inositol trisphosphate signalling cascade by catalysing the final dephosphorylation of inositol and has been implicated in the therapeutic mechanism of lithium treatment of bipolar disorder. Previously studies have shown that calbindin-D28k can increase IMPase activity by up to 250 hundred-fold. A preliminary in silico model was proposed for the interaction. Here, we aimed at exploring the shape and properties of the calbindin-IMPase complex to gain new insights on this biologically important interaction. We created several fusion constructs of calbindin-D28k and IMPase, connected by flexible amino acid linkers of different lengths and orientations to fuse the termini of the two proteins together. The resulting fusion proteins have activities 200%–400% higher the isolated wild-type IMPase. The constructs were characterized by small angle X-ray scattering to gain information on the overall shape of the complexes and validate the previous model. The fusion proteins form a V-shaped, elongated and less compact complex as compared to the model. Our results shed new light into this protein-protein interaction.	Jul 2022
I03-Macromolecular Crystallography	Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15 Maria Giulia Nizi , Mirko M. Maksimainen , Sudarshan Murthy , Serena Massari , Juho Alaviuhkola , Barbara E. Lippok , Sven T. Sowa , Albert Galera-Prat , Renata Prunskaite-Hyyryläinen , Bernhard Lüscher , Patricia Korn , Lari Lehtio , Oriana Tabarrini European Journal Of Medicinal Chemistry 237 DOI: 10.1016/j.ejmech.2022.114362 Diamond Proposal Number(s): [19951] Show Abstract ▼ Abstract: While human poly-ADP-ribose chain generating poly-ARTs, PARP1 and 2 and TNKS1 and 2, have been widely characterized, less is known on the pathophysiological roles of the mono-ADP-ribosylating mono-ARTs, partly due to the lack of selective inhibitors. In this context, we have focused on the development of inhibitors for the mono-ART PARP10, whose overexpression is known to induce cell death. Starting from OUL35 (1) and its 4-(benzyloxy)benzamidic derivative (2) we herein report the design and synthesis of new analogues from which the cyclobutyl derivative 3c rescued cells most efficiently from PARP10 induced apoptosis. Most importantly, we also identified 2,3-dihydrophthalazine-1,4-dione as a new suitable nicotinamide mimicking PARP10 inhibitor scaffold. When it was functionalized with cycloalkyl (8a-c), o-fluorophenyl (8h), and thiophene (8l) rings, IC50 values in the 130–160 nM range were obtained, making them the most potent PARP10 inhibitors reported to date. These compounds also inhibited PARP15 with low micromolar IC50s, but none of the other tested poly- and mono-ARTs, thus emerging as dual mono-ART inhibitors. Compounds 8a, 8h and 8l were also able to enter cells and rescue cells from apoptosis. Our work sheds more light on inhibitor development against mono-ARTs and identifies chemical probes to study the cellular roles of PARP10 and PARP15.	Jul 2022
B21-High Throughput SAXS	Biophysical characterisation of human LincRNA-p21 sense and antisense Alu inverted repeats Michael H D'Souza , Tyler Mrozowich , Maulik D. Badmalia , Mitchell Geeraert , Angela Frederickson , Amy Henrickson , Borries Demeler , Michael t. Wolfinger , Trushar R. Patel Nucleic Acids Research 50, 5881 - 5898 DOI: 10.1093/nar/gkac414 Diamond Proposal Number(s): [26855] Open Access Show Abstract ▼ Abstract: Human Long Intergenic Noncoding RNA-p21 (LincRNA-p21) is a regulatory noncoding RNA that plays an important role in promoting apoptosis. LincRNA-p21 is also critical in down-regulating many p53 target genes through its interaction with a p53 repressive complex. The interaction between LincRNA-p21 and the repressive complex is likely dependent on the RNA tertiary structure. Previous studies have determined the two-dimensional secondary structures of the sense and antisense human LincRNA-p21 AluSx1 IRs using SHAPE. However, there were no insights into its three-dimensional structure. Therefore, we in vitro transcribed the sense and antisense regions of LincRNA-p21 AluSx1 Inverted Repeats (IRs) and performed analytical ultracentrifugation, size exclusion chromatography, light scattering, and small angle X-ray scattering (SAXS) studies. Based on these studies, we determined low-resolution, three-dimensional structures of sense and antisense LincRNA-p21. By adapting previously known two-dimensional information, we calculated their sense and antisense high-resolution models and determined that they agree with the low-resolution structures determined using SAXS. Thus, our integrated approach provides insights into the structure of LincRNA-p21 Alu IRs. Our study also offers a viable pipeline for combining the secondary structure information with biophysical and computational studies to obtain high-resolution atomistic models for long noncoding RNAs.	Jun 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Optimizing shape complementarity enables the discovery of potent tricyclic BCL6 inhibitors Owen A. Davis , Kwai-Ming J. Cheung , Alfie Brennan , Matthew G. Lloyd , Matthew J. Rodrigues , Olivier A. Pierrat , Gavin W. Collie , Yann-Vai Le Bihan , Rosemary Huckvale , Alice C. Harnden , Ana Varela , Michael D. Bright , Paul Eve , Angela Hayes , Alan T. Henley , Michael D. Carter , P. Craig Mcandrew , Rachel Talbot , Rosemary Burke , Rob Van Montfort , Florence I. Raynaud , Olivia W. Rossanese , Mirco Meniconi , Benjamin R. Bellenie , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c02174 Open Access Show Abstract ▼ Abstract: To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.	Jun 2022
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural analysis and development of notum fragment screening hits Yuguang Zhao , William Mahy , Nicky J. Willis , Hannah L. Woodward , David Steadman , Elliott D. Bayle , Benjamin N. Atkinson , James Sipthorp , Luca Vecchia , Reinis R. Ruza , Karl Harlos , Fiona Jeganathan , Stefan Constantinou , Artur Costa , Svend Kjær , Magda Bictash , Patricia C. Salinas , Paul Whiting , Jean-Paul Vincent , Paul V. Fish , E. Yvonne Jones Acs Chemical Neuroscience DOI: 10.1021/acschemneuro.2c00325 Diamond Proposal Number(s): [16814] Open Access Show Abstract ▼ Abstract: The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer’s disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments’ diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.	Jun 2022
I03-Macromolecular Crystallography	Improved binding affinity and pharmacokinetics enable sustained degradation of BCL6 in vivo Rosemary Huckvale , Alice C. Harnden , Kwai-Ming J. Cheung , Olivier A. Pierrat , Rachel Talbot , Gary M. Box , Alan T. Henley , Alexis K. De Haven Brandon , Albert E. Hallsworth , Michael D. Bright , Hafize Aysin Akpinar , Daniel S. J. Miller , Dalia Tarantino , Sharon Gowan , Angela Hayes , Emma A. Gunnell , Alfie Brennan , Owen A. Davis , Louise D. Johnson , Selby De Klerk , Craig Mcandrew , Yann-Vai Le Bihan , Mirco Meniconi , Rosemary Burke , Vladimir Kirkin , Rob L. M. Van Montfort , Florence I. Raynaud , Olivia W. Rossanese , Benjamin R. Bellenie , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c02175 Open Access Show Abstract ▼ Abstract: The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.	Jun 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
I07-Surface & interface diffraction	Nondestructive compression and fluidization of phospholipid monolayers by gaseous and aerolized perfluorocarbons: promising substances for lung surfactant treatment Susanne Dogan , Michael Paulus , Goran Surmeier , Kevin Foryt , Katharina Brägelmann , Metin Tolan Langmuir DOI: 10.1021/acs.langmuir.2c00617 Diamond Proposal Number(s): [20529] Show Abstract ▼ Abstract: We present a surface-sensitive X-ray scattering study on the influence of gaseous and aerolized perfluorocarbons (FCs) on zwitterionic and anionic phospholipid Langmuir films, which serve as a simplified model system of lung surfactants. It was found that small gaseous FC molecules like F-propane and F-butane penetrate phospholipid monolayers and accumulate between the alkyl chains and form islands. This clustering process can trigger the formation of lipid crystallites at low initial surface pressures. In contrast, the large linear FC F-octyl bromide fluidizes membranes, causing a dissolution of crystalline domains. The bicyclic FC F-decalin accumulates between the alkyl chains of 1,2-dipalmitoyl phosphatidylcholine but cannot penetrate the more densely packed 1,2-dipalmitoyl phosphatidic acid films because of its size. The effects of FCs on lung surfactants are discussed in the framework of currently proposed therapeutic methods for acute respiratory distress syndrome using FC gases, vapor, or aerosol ventilation causing monolayer fluidization effects. This study implies that the highly biocompatible and nontoxic FCs could be beneficial in the treatment of lung diseases with injured nonfunctional lung surfactants in a novel approach for ventilation.	May 2022
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10 Jingxu Guo , Bin Liu , Midory Thorikay , Minmin Yu , Xiaoyan Li , Zhen Tong , Richard M. Salmon , Randy Read , Peter Ten Dijke , Nicholas W. Morrell , Wei Li Nature Communications 13 DOI: 10.1038/s41467-022-30111-2 Diamond Proposal Number(s): [21426] Open Access Show Abstract ▼ Abstract: Heterozygous mutations in BMPR2 (bone morphogenetic protein (BMP) receptor type II) cause pulmonary arterial hypertension. BMPRII is a receptor for over 15 BMP ligands, but why BMPR2 mutations cause lung-specific pathology is unknown. To elucidate the molecular basis of BMP:BMPRII interactions, we report crystal structures of binary and ternary BMPRII receptor complexes with BMP10, which contain an ensemble of seven different BMP10:BMPRII 1:1 complexes. BMPRII binds BMP10 at the knuckle epitope, with the A-loop and β4 strand making BMPRII-specific interactions. The BMPRII binding surface on BMP10 is dynamic, and the affinity is weaker in the ternary complex than in the binary complex. Hydrophobic core and A-loop interactions are important in BMPRII-mediated signalling. Our data reveal how BMPRII is a low affinity receptor, implying that forming a signalling complex requires high concentrations of BMPRII, hence mutations will impact on tissues with highest BMPR2 expression such as the lung vasculature.	May 2022
I04-Macromolecular Crystallography	Discovery of AZD4625, a covalent allosteric inhibitor of the mutant GTPase KRASG12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Scott Boyd , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Nichola L. Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma S. Gleave , Frederick W. Goldberg , Lyndsey Hanson , Stephanie Harlfinger , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Gillian Lamont , Scott Lamont , Hilary J. Lewis , Libin Liu , Michael J. Niedbala , Christopher Phillips , Radek Polanski , Piotr Raubo , Graeme Robb , David M. Robinson , Sarah Ross , Matthew G. Sanders , Michael Tonge , Rebecca Whiteley , Stephen Wilkinson , Junsheng Yang , Wenman Zhang Journal Of Medicinal Chemistry 65, 6940 - 6952 DOI: 10.1021/acs.jmedchem.2c00369 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.	May 2022

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