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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Glutathione facilitates enterovirus assembly by binding at a druggable pocket Helen M. E. Duyvesteyn , Jingshan Ren , Thomas S. Walter , Elizabeth E. Fry , David I. Stuart Communications Biology 3 DOI: 10.1038/s42003-019-0722-x Diamond Proposal Number(s): [19946] Open Access Show Abstract ▼ Abstract: Enteroviruses cause a range of human and animal diseases, some life-threatening, but there remain no licenced anti-enterovirus drugs. However, a benzene-sulfonamide derivative and related compounds have been shown recently to block infection of a range of enteroviruses by binding the capsid at a positively-charged surface depression conserved across many enteroviruses. It has also been established that glutathione is essential for the assembly of many enteroviruses, interacting with the capsid proteins to facilitate the formation of the pentameric assembly intermediate, although the mechanism is unknown. Here we show, by high resolution structure analyses of enterovirus F3, that reduced glutathione binds to the same interprotomer pocket as the benzene-sulfonamide derivative. Bound glutathione makes strong interactions with adjacent protomers, thereby explaining the underlying biological role of this druggable binding pocket and delineating the pharmacophore for potential antivirals.	Jan 2020
I04-Macromolecular Crystallography	High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity Wen Zhu , Ashish Radadiya , Claudine Bisson , Sabine Wenzel , Brian E. Nordin , Francisco Martínez-márquez , Tsuyoshi Imasaki , Svetlana E. Sedelnikova , Adriana Coricello , Patrick Baumann , Alexandria H. Berry , Tyzoon K. Nomanbhoy , John W. Kozarich , Yi Jin , David W. Rice , Yuichiro Takagi , Nigel G. J. Richards Communications Biology 2 DOI: 10.1038/s42003-019-0587-z Diamond Proposal Number(s): [12788] Open Access Show Abstract ▼ Abstract: Expression of human asparagine synthetase (ASNS) promotes metastatic progression and tumor cell invasiveness in colorectal and breast cancer, presumably by altering cellular levels of L-asparagine. Human ASNS is therefore emerging as a bona fide drug target for cancer therapy. Here we show that a slow-onset, tight binding inhibitor, which exhibits nanomolar affinity for human ASNS in vitro, exhibits excellent selectivity at 10 μM concentration in HCT-116 cell lysates with almost no off-target binding. The high-resolution (1.85 Å) crystal structure of human ASNS has enabled us to identify a cluster of negatively charged side chains in the synthetase domain that plays a key role in inhibitor binding. Comparing this structure with those of evolutionarily related AMP-forming enzymes provides insights into intermolecular interactions that give rise to the observed binding selectivity. Our findings demonstrate the feasibility of developing second generation human ASNS inhibitors as lead compounds for the discovery of drugs against metastasis.	Sep 2019
I04-Macromolecular Crystallography	High-resolution crystal structure of arthropod Eiger TNF suggests a mode of receptor engagement and altered surface charge within endosomes Mattia Bertinelli , Guido C. Paesen , Jonathan M. Grimes , Max Renner Communications Biology 2 DOI: 10.1038/s42003-019-0541-0 Diamond Proposal Number(s): [14774] Open Access Show Abstract ▼ Abstract: The tumour necrosis factor alpha (TNFα) superfamily of proteins are critical in numerous biological processes, such as in development and immunity. Eiger is the sole TNFα member described in arthropods such as in the important model organism Drosophila. To date there are no structural data on any Eiger protein. Here we present the structure of the TNF domain of Eiger from the fall armyworm Spodoptera frugiperda (SfEiger) to 1.7 Å from a serendipitously obtained crystal without prior knowledge of the protein sequence. Our structure confirms that canonical trimerization is conserved from ancestral TNFs and points towards a mode of receptor engagement. Furthermore, we observe numerous surface histidines on SfEiger, potentially acting as pH switches following internalization into endosomes. Our data contributes to the genome annotation of S. frugiperda, a voracious agricultural pest, and can serve as a basis for future structure-function investigations of the TNF system in related arthropods such as Drosophila.	Aug 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites Shaowei Zhang , Michiyo Sakuma , Girdhar S. Deora , Colin Levy , Alex Klausing , Carlo Breda , Kevin D. Read , Chris D. Edlin , Benjamin P. Ross , Marina Wright Muelas , Philip J. Day , Stephen O’hagan , Douglas B. Kell , Robert Schwarcz , David Leys , Derren J. Heyes , Flaviano Giorgini , Nigel S. Scrutton Communications Biology 2 DOI: 10.1038/s42003-019-0520-5 Diamond Proposal Number(s): [8997, 12788] Open Access Show Abstract ▼ Abstract: Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood–brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.	Jul 2019
Krios II-Titan Krios II at Diamond	Cryo-EM and directed evolution reveal how Arabidopsis nitrilase specificity is influenced by its quaternary structure Andani Mulelu , Angela Kirykowicz , Jeremy Woodward Communications Biology 2 DOI: 10.1038/s42003-019-0505-4 PMID: 31341959 Diamond Proposal Number(s): [20975] Open Access Show Abstract ▼ Abstract: Nitrilases are helical enzymes that convert nitriles to acids and/or amides. All plants have a nitrilase 4 homolog specific for ß-cyanoalanine, while in some plants neofunctionalization has produced nitrilases with altered specificity. Plant nitrilase substrate size and specificity correlate with helical twist, but molecular details of this relationship are lacking. Here we determine, to our knowledge, the first close-to-atomic resolution (3.4 Å) cryo-EM structure of an active helical nitrilase, the nitrilase 4 from Arabidopsis thaliana. We apply site-saturation mutagenesis directed evolution to three residues (R95, S224, and L169) and generate a mutant with an altered helical twist that accepts substrates not catalyzed by known plant nitrilases. We reveal that a loop between α2 and α3 limits the length of the binding pocket and propose that it shifts position as a function of helical twist. These insights will allow us to start designing nitrilases for chemoenzymatic synthesis.	Jul 2019
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism Giancarlo Abis , Rebecca L. Charles , Jolanta Kopec , Wyatt W. Yue , R. Andrew Atkinson , Tam T. T. Bui , Steven Lynham , Simona Popova , Yin-biao Sun , Franca Fraternali , Philip Eaton , Maria R. Conte Communications Biology 2 DOI: 10.1038/s42003-019-0426-2 Diamond Proposal Number(s): [13597, 10619] Open Access Show Abstract ▼ Abstract: Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors.	May 2019
I24-Microfocus Macromolecular Crystallography	Structure of Mycobacterium tuberculosis phosphatidylinositol phosphate synthase reveals mechanism of substrate binding and metal catalysis Kristine Grave , Matthew D. Bennett , Martin Högbom Communications Biology 2 DOI: 10.1038/s42003-019-0427-1 Diamond Proposal Number(s): [11265] Open Access Show Abstract ▼ Abstract: Tuberculosis causes over one million yearly deaths, and drug resistance is rapidly developing. Mycobacterium tuberculosis phosphatidylinositol phosphate synthase (PgsA1) is an integral membrane enzyme involved in biosynthesis of inositol-derived phospholipids required for formation of the mycobacterial cell wall, and a potential drug target. Here we present three crystal structures of M. tuberculosis PgsA1: in absence of substrates (2.9 Å), in complex with Mn2+ and citrate (1.9 Å), and with the CDP-DAG substrate (1.8 Å). The structures reveal atomic details of substrate binding as well as coordination and dynamics of the catalytic metal site. In addition, molecular docking supported by mutagenesis indicate a binding mode for the second substrate, D-myo-inositol-3-phosphate. Together, the data describe the structural basis for M. tuberculosis phosphatidylinositol phosphate synthesis and suggest a refined general catalytic mechanism—including a substrate-induced carboxylate shift—for Class I CDP-alcohol phosphotransferases, enzymes essential for phospholipid biosynthesis in all domains of life.	May 2019

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