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274 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
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Inverting family GH156 sialidases define an unusual catalytic motif for glycosidase action Pedro Bule , Léa Chuzel , Elena Blagova , Liang Wu , Melissa A. Gray , Bernard Henrissat , Erdmann Rapp , Carolyn R. Bertozzi , Christopher H. Taron , Gideon J. Davies Nature Communications 10 DOI: 10.1038/s41467-019-12684-7 Diamond Proposal Number(s): [18598] Open Access Show Abstract ▼ Abstract: Sialic acids are a family of related sugars that play essential roles in many biological events intimately linked to cellular recognition in both health and disease. Sialidases are therefore orchestrators of cellular biology and important therapeutic targets for viral infection. Here, we sought to define if uncharacterized sialidases would provide distinct paradigms in sialic acid biochemistry. We show that a recently discovered sialidase family, whose first member EnvSia156 was isolated from hot spring metagenomes, defines an unusual structural fold and active centre constellation, not previously described in sialidases. Consistent with an inverting mechanism, EnvSia156 reveals a His/Asp active center in which the His acts as a Brønsted acid and Asp as a Brønsted base in a single-displacement mechanism. A predominantly hydrophobic aglycone site facilitates accommodation of a variety of 2-linked sialosides; a versatility that offers the potential for glycan hydrolysis across a range of biological and technological platforms.	Oct 2019
I04-Macromolecular Crystallography	A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases Leo Kiss , Jingwei Zeng , Claire Dickson , Donna L. Mallery , Ji-chun Yang , Stephen H. Mclaughlin , Andreas Boland , David Neuhaus , Leo C. James Nature Communications 10 DOI: 10.1038/s41467-019-12388-y Diamond Proposal Number(s): [15916] Open Access Show Abstract ▼ Abstract: The cytosolic antibody receptor TRIM21 possesses unique ubiquitination activity that drives broad-spectrum anti-pathogen targeting and underpins the protein depletion technology Trim-Away. This activity is dependent on formation of self-anchored, K63-linked ubiquitin chains by the heterodimeric E2 enzyme Ube2N/Ube2V2. Here we reveal how TRIM21 facilitates ubiquitin transfer and differentiates this E2 from other closely related enzymes. A tri-ionic motif provides optimally distributed anchor points that allow TRIM21 to wrap an Ube2N~Ub complex around its RING domain, locking the closed conformation and promoting ubiquitin discharge. Mutation of these anchor points inhibits ubiquitination with Ube2N/Ube2V2, viral neutralization and immune signalling. We show that the same mechanism is employed by the anti-HIV restriction factor TRIM5 and identify spatially conserved ionic anchor points in other Ube2N-recruiting RING E3s. The tri-ionic motif is exclusively required for Ube2N but not Ube2D1 activity and provides a generic E2-specific catalysis mechanism for RING E3s.	Oct 2019
B21-High Throughput SAXS	Aldehyde-alcohol dehydrogenase forms a high-order spirosome architecture critical for its activity Gijeong Kim , Liyana Azmi , Seongmin Jang , Taeyang Jung , Hans Hebert , Andrew J. Roe , Olwyn Byron , Ji-joon Song Nature Communications 10 DOI: 10.1038/s41467-019-12427-8 Diamond Proposal Number(s): [21440] Open Access Show Abstract ▼ Abstract: Aldehyde-alcohol dehydrogenase (AdhE) is a key enzyme in bacterial fermentation, converting acetyl-CoA to ethanol, via two consecutive catalytic reactions. Here, we present a 3.5 Å resolution cryo-EM structure of full-length AdhE revealing a high-order spirosome architecture. The structure shows that the aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) active sites reside at the outer surface and the inner surface of the spirosome respectively, thus topologically separating these two activities. Furthermore, mutations disrupting the helical structure abrogate enzymatic activity, implying that formation of the spirosome structure is critical for AdhE activity. In addition, we show that this spirosome structure undergoes conformational change in the presence of cofactors. This work presents the atomic resolution structure of AdhE and suggests that the high-order helical structure regulates its enzymatic activity.	Oct 2019
B18-Core EXAFS	The rapid electrochemical activation of MoTe2 for the hydrogen evolution reaction Jessica C. Mcglynn , Torben Dankwort , Lorenz Kienle , Nuno A. G. Bandeira , James P. Fraser , Emma K. Gibson , Irene Cascallana-matias , Katalin Kamarás , Mark D. Symes , Harry N. Miras , Alexey Y. Ganin Nature Communications 10 DOI: 10.1038/s41467-019-12831-0 Diamond Proposal Number(s): [14239] Open Access Show Abstract ▼ Abstract: The electrochemical generation of hydrogen is a key enabling technology for the production of sustainable fuels. Transition metal chalcogenides show considerable promise as catalysts for this reaction, but to date there are very few reports of tellurides in this context, and none of these transition metal telluride catalysts are especially active. Here, we show that the catalytic performance of metallic 1T′-MoTe2 is improved dramatically when the electrode is held at cathodic bias. As a result, the overpotential required to maintain a current density of 10 mA cm−2 decreases from 320 mV to just 178 mV. We show that this rapid and reversible activation process has its origins in adsorption of H onto Te sites on the surface of 1T′-MoTe2. This activation process highlights the importance of subtle changes in the electronic structure of an electrode material and how these can influence the subsequent electrocatalytic activity that is displayed.	Oct 2019
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern Inga Pfeffer , Lennart Brewitz , Tobias Krojer , Sacha A. Jensen , Grazyna T. Kochan , Nadia J. Kershaw , Kirsty S. Hewitson , Luke A. Mcneill , Holger Kramer , Martin Münzel , Richard J. Hopkinson , Udo Oppermann , Penny A. Handford , Michael A. Mcdonough , Christopher J. Schofield Nature Communications 10 DOI: 10.1038/s41467-019-12711-7 Open Access Show Abstract ▼ Abstract: AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern; an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases.	Oct 2019
B22-Multimode InfraRed imaging And Microspectroscopy	Integration of mesopores and crystal defects in metal-organic frameworks via templated electrosynthesis Xinchen Kang , Kai Lyu , Lili Li , Jiangnan Li , Louis Kimberley , Bin Wang , Lifei Liu , Yongqiang Cheng , Mark D. Frogley , Svemir Rudic , Anibal J. Ramirez-cuesta , Robert A. W. Dryfe , Buxing Han , Sihai Yang , Martin Schroder Nature Communications 10 DOI: 10.1038/s41467-019-12268-5 Diamond Proposal Number(s): [19171] Open Access Show Abstract ▼ Abstract: Incorporation of mesopores and active sites into metal-organic framework (MOF) materials to uncover new efficient catalysts is a highly desirable but challenging task. We report the first example of a mesoporous MOF obtained by templated electrosynthesis using an ionic liquid as both electrolyte and template. The mesoporous Cu(II)-MOF MFM-100 has been synthesised in 100 seconds at room temperature, and this material incorporates crystal defects with uncoupled Cu(II) centres as evidenced by confocal fluorescence microscopy and electron paramagnetic resonance spectroscopy. MFM-100 prepared in this way shows exceptional catalytic activity for the aerobic oxidation of alcohols to produce aldehydes in near quantitative yield and selectivity under mild conditions, as well as having excellent stability and reusability over repeated cycles. The catalyst-substrate binding interactions have been probed by inelastic neutron scattering. This study offers a simple strategy to create mesopores and active sites simultaneously via electrochemical formation of crystal defects to promote efficient catalysis using MOFs.	Oct 2019
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo Joshua L. C. Wong , Maria Romano , Louise E. Kerry , Hok-sau Kwong , Wen-wen Low , Stephen J. Brett , Abigail Clements , Konstantinos Beis , Gad Frankel Nature Communications 10 DOI: 10.1038/s41467-019-11756-y Diamond Proposal Number(s): [17221] Open Access Show Abstract ▼ Abstract: Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes on pathogenicity remain unknown. By solving the crystal structure of a clinical ST258 OmpK36 variant we provide direct structural evidence of pore constriction, mediated by a di-amino acid (Gly115-Asp116) insertion into loop 3, restricting diffusion of both nutrients (e.g. lactose) and Carbapenems. In the presence of KPC-2 this results in a 16-fold increase in MIC to Meropenem. Additionally, the Gly-Asp insertion impairs bacterial growth in lactose-containing medium and confers a significant in vivo fitness cost in a murine model of ventilator-associated pneumonia. Our data suggests that the continuous selective pressure imposed by widespread Carbapenem utilisation in hospital settings drives the expansion of KP expressing Gly-Asp insertion mutants, despite an associated fitness cost.	Sep 2019
I24-Microfocus Macromolecular Crystallography	The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K Simon R. Bushell , Ashley C. W. Pike , Maria E. Falzone , Nils J. G. Rorsman , Chau M. Ta , Robin A. Corey , Thomas D. Newport , John C. Christianson , Lara F. Scofano , Chitra Shintre , Annamaria Tessitore , Amy Chu , Qinrui Wang , Leela Shrestha , Shubhashish M. M. Mukhopadhyay , James D. Love , Nicola A. Burgess-brown , Rebecca Sitsapesan , Phillip J. Stansfeld , Juha T. Huiskonen , Paolo Tammaro , Alessio Accardi , Elisabeth P. Carpenter Nature Communications 10 DOI: 10.1038/s41467-019-11753-1 Diamond Proposal Number(s): [10619, 15433] Open Access Show Abstract ▼ Abstract: Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.	Sep 2019
Krios I-Titan Krios I at Diamond	Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome Sarah V. Faull , Andy M. C. Lau , Chloe Martens , Zainab Ahdash , Kjetil Hansen , Hugo Yebenes , Carla Schmidt , Fabienne Beuron , Nora B. Cronin , Edward Morris , Argyris Politis Nature Communications 10 DOI: 10.1038/s41467-019-11772-y Diamond Proposal Number(s): [15621, 16023] Open Access Show Abstract ▼ Abstract: Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members.	Sep 2019
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural basis for activation of a diguanylate cyclase required for bacterial predation in Bdellovibrio Richard W. Meek , Ian T. Cadby , Patrick J. Moynihan , Andrew K. Lovering Nature Communications 10 DOI: 10.1038/s41467-019-12051-6 Diamond Proposal Number(s): [10369, 14692] Open Access Show Abstract ▼ Abstract: The bacterial second messenger cyclic-di-GMP is a widespread, prominent effector of lifestyle change. An example of this occurs in the predatory bacterium Bdellovibrio bacteriovorus, which cycles between free-living and intraperiplasmic phases after entering (and killing) another bacterium. The initiation of prey invasion is governed by DgcB (GGDEF enzyme) that produces cyclic-di-GMP in response to an unknown stimulus. Here, we report the structure of DgcB, and demonstrate that the GGDEF and sensory forkhead-associated (FHA) domains form an asymmetric dimer. Our structures indicate that the FHA domain is a consensus phosphopeptide sensor, and that the ligand for activation is surprisingly derived from the N-terminal region of DgcB itself. We confirm this hypothesis by determining the structure of a FHA:phosphopeptide complex, from which we design a constitutively-active mutant (confirmed via enzyme assays). Our results provide an understanding of the stimulus driving DgcB-mediated prey invasion and detail a unique mechanism of GGDEF enzyme regulation.	Sep 2019

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