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313 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 I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release Henry J. Bailey , Gustavo A. Bezerra , Jason R. Marcero , Siladitya Padhi , William R. Foster , Elzbieta Rembeza , Arijit Roy , David F. Bishop , Robert J. Desnick , Gopalakrishnan Bulusu , Harry A. Dailey , Wyatt W. Yue Nature Communications 11 DOI: 10.1038/s41467-020-16586-x Open Access Show Abstract ▼ Abstract: 5′-aminolevulinate synthase (ALAS) catalyzes the first step in heme biosynthesis, generating 5′-aminolevulinate from glycine and succinyl-CoA. Inherited frameshift indel mutations of human erythroid-specific isozyme ALAS2, within a C-terminal (Ct) extension of its catalytic core that is only present in higher eukaryotes, lead to gain-of-function X-linked protoporphyria (XLP). Here, we report the human ALAS2 crystal structure, revealing that its Ct-extension folds onto the catalytic core, sits atop the active site, and precludes binding of substrate succinyl-CoA. The Ct-extension is therefore an autoinhibitory element that must re-orient during catalysis, as supported by molecular dynamics simulations. Our data explain how Ct deletions in XLP alleviate autoinhibition and increase enzyme activity. Crystallography-based fragment screening reveals a binding hotspot around the Ct-extension, where fragments interfere with the Ct conformational dynamics and inhibit ALAS2 activity. These fragments represent a starting point to develop ALAS2 inhibitors as substrate reduction therapy for porphyria disorders that accumulate toxic heme intermediates.	Jun 2020
Krios IV-Titan Krios IV at Diamond	Mechanism of effector capture and delivery by the type IV secretion system from Legionella pneumophila Amit Meir , Kevin Mace , Natalya Lukoyanova , David Chetrit , Manuela K. Hospenthal , Adam Redzej , Craig Roy , Gabriel Waksman Nature Communications 11 DOI: 10.1038/s41467-020-16681-z Diamond Proposal Number(s): [14704] Open Access Show Abstract ▼ Abstract: Legionella pneumophila is a bacterial pathogen that utilises a Type IV secretion (T4S) system to inject effector proteins into human macrophages. Essential to the recruitment and delivery of effectors to the T4S machinery is the membrane-embedded T4 coupling complex (T4CC). Here, we purify an intact T4CC from the Legionella membrane. It contains the DotL ATPase, the DotM and DotN proteins, the chaperone module IcmSW, and two previously uncharacterised proteins, DotY and DotZ. The atomic resolution structure reveals a DotLMNYZ hetero-pentameric core from which the flexible IcmSW module protrudes. Six of these hetero-pentameric complexes may assemble into a 1.6-MDa hexameric nanomachine, forming an inner membrane channel for effectors to pass through. Analysis of multiple cryo EM maps, further modelling and mutagenesis provide working models for the mechanism for binding and delivery of two essential classes of Legionella effectors, depending on IcmSW or DotM, respectively.	Jun 2020
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	An evolutionary path to altered cofactor specificity in a metalloenzyme Anna Barwinska-sendra , Yuritzi M. Garcia , Kacper M. Sendra , Arnaud Basle , Eilidh S. Mackenzie , Emma Tarrant , Patrick Card , Leandro C. Tabares , Cédric Bicep , Sun Un , Thomas E. Kehl-fie , Kevin J. Waldron Nature Communications 11 DOI: 10.1038/s41467-020-16478-0 Diamond Proposal Number(s): [7864, 9948, 18598] Open Access Show Abstract ▼ Abstract: Almost half of all enzymes utilize a metal cofactor. However, the features that dictate the metal utilized by metalloenzymes are poorly understood, limiting our ability to manipulate these enzymes for industrial and health-associated applications. The ubiquitous iron/manganese superoxide dismutase (SOD) family exemplifies this deficit, as the specific metal used by any family member cannot be predicted. Biochemical, structural and paramagnetic analysis of two evolutionarily related SODs with different metal specificity produced by the pathogenic bacterium Staphylococcus aureus identifies two positions that control metal specificity. These residues make no direct contacts with the metal-coordinating ligands but control the metal’s redox properties, demonstrating that subtle architectural changes can dramatically alter metal utilization. Introducing these mutations into S. aureus alters the ability of the bacterium to resist superoxide stress when metal starved by the host, revealing that small changes in metal-dependent activity can drive the evolution of metalloenzymes with new cofactor specificity.	Jun 2020
E02-JEM ARM 300CF	Low-dose phase retrieval of biological specimens using cryo-electron ptychography Liqi Zhou , Jingdong Song , Judy S. Kim , Xudong Pei , Chen Huang , Mark Boyce , Luiza Mendonca , Daniel Clare , Alistair Siebert , Christopher Allen , Emanuela Liberti , David Stuart , Xiaoqing Pan , Peter Nellist , Peijun Zhang , Angus Kirkland , Peng Wang Nature Communications 11 DOI: 10.1038/s41467-020-16391-6 Diamond Proposal Number(s): [19243, 20431, 20961, 22317] Open Access Show Abstract ▼ Abstract: Cryo-electron microscopy is an essential tool for high-resolution structural studies of biological systems. This method relies on the use of phase contrast imaging at high defocus to improve information transfer at low spatial frequencies at the expense of higher spatial frequencies. Here we demonstrate that electron ptychography can recover the phase of the specimen with continuous information transfer across a wide range of the spatial frequency spectrum, with improved transfer at lower spatial frequencies, and as such is more efficient for phase recovery than conventional phase contrast imaging. We further show that the method can be used to study frozen-hydrated specimens of rotavirus double-layered particles and HIV-1 virus-like particles under low-dose conditions (5.7 e/Å2) and heterogeneous objects in an Adenovirus-infected cell over large fields of view (1.14 × 1.14 μm), thus making it suitable for studies of many biologically important structures.	Jun 2020
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	The receptor PTPRU is a redox sensitive pseudophosphatase Iain M. Hay , Gareth W. Fearnley , Pablo Rios , Maja Köhn , Hayley J. Sharpe , Janet E. Deane Nature Communications 11 DOI: 10.1038/s41467-020-17076-w Diamond Proposal Number(s): [15916] Open Access Show Abstract ▼ Abstract: The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal (D1) domain and an inactive distal (D2) pseudophosphatase domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal “backdoor” cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.	Jun 2020
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis Elizabeth R. Morris , Sarah J. Caswell , Simone Kunzelmann , Laurence H. Arnold , Andrew G. Purkiss , Geoff Kelly , Ian A. Taylor Nature Communications 11 DOI: 10.1038/s41467-020-16983-2 Diamond Proposal Number(s): [13775, 18566] Open Access Show Abstract ▼ Abstract: SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate. In CD4+ myeloid lineage and resting T-cells, SAMHD1 blocks HIV-1 and other viral infections by depletion of the dNTP pool to a level that cannot support replication. SAMHD1 mutations are associated with the autoimmune disease Aicardi–Goutières syndrome and hypermutated cancers. Furthermore, SAMHD1 sensitises cancer cells to nucleoside-analogue anti-cancer therapies and is linked with DNA repair and suppression of the interferon response to cytosolic nucleic acids. Nevertheless, despite its requirement in these processes, the fundamental mechanism of SAMHD1-catalysed dNTP hydrolysis remained unknown. Here, we present structural and enzymological data showing that SAMHD1 utilises an active site, bi-metallic iron-magnesium centre that positions a hydroxide nucleophile in-line with the Pα-O5′ bond to catalyse phosphoester bond hydrolysis. This precise molecular mechanism for SAMHD1 catalysis, reveals how SAMHD1 down-regulates cellular dNTP and modulates the efficacy of nucleoside-based anti-cancer and anti-viral therapies.	Jun 2020
I06-Nanoscience	Large magnetoelectric coupling in multiferroic oxide heterostructures assembled via epitaxial lift-off D. Pesquera , E. Khestanova , M. Ghidini , S. Zhang , A. P. Rooney , F. Maccherozzi , P. Riego , S. Farokhipoor , J. Kim , X. Moya , M. E. Vickers , N. A. Stelmashenko , S. J. Haigh , S. S. Dhesi , N. D. Mathur Nature Communications 11 DOI: 10.1038/s41467-020-16942-x Diamond Proposal Number(s): [14745] Open Access Show Abstract ▼ Abstract: Epitaxial films may be released from growth substrates and transferred to structurally and chemically incompatible substrates, but epitaxial films of transition metal perovskite oxides have not been transferred to electroactive substrates for voltage control of their myriad functional properties. Here we demonstrate good strain transmission at the incoherent interface between a strain-released film of epitaxially grown ferromagnetic La0.7Sr0.3MnO3 and an electroactive substrate of ferroelectric 0.68Pb(Mg1/3Nb2/3)O3-0.32PbTiO3 in a different crystallographic orientation. Our strain-mediated magnetoelectric coupling compares well with respect to epitaxial heterostructures, where the epitaxy responsible for strong coupling can degrade film magnetization via strain and dislocations. Moreover, the electrical switching of magnetic anisotropy is repeatable and non-volatile. High-resolution magnetic vector maps reveal that micromagnetic behaviour is governed by electrically controlled strain and cracks in the film. Our demonstration should inspire others to control the physical/chemical properties in strain-released epitaxial oxide films by using electroactive substrates to impart strain via non-epitaxial interfaces.	Jun 2020
Krios II-Titan Krios II at Diamond	Cryo-electron microscopy reveals two distinct type IV pili assembled by the same bacterium Alexander Neuhaus , Muniyandi Selvaraj , Ralf Salzer , Julian D. Langer , Kerstin Kruse , Lennart Kirchner , Kelly Sanders , Bertram Daum , Beate Averhoff , Vicki A. M. Gold Nature Communications 11 DOI: 10.1038/s41467-020-15650-w Diamond Proposal Number(s): [18258] Open Access Show Abstract ▼ Abstract: Type IV pili are flexible filaments on the surface of bacteria, consisting of a helical assembly of pilin proteins. They are involved in bacterial motility (twitching), surface adhesion, biofilm formation and DNA uptake (natural transformation). Here, we use cryo-electron microscopy and mass spectrometry to show that the bacterium Thermus thermophilus produces two forms of type IV pilus (‘wide’ and ‘narrow’), differing in structure and protein composition. Wide pili are composed of the major pilin PilA4, while narrow pili are composed of a so-far uncharacterized pilin which we name PilA5. Functional experiments indicate that PilA4 is required for natural transformation, while PilA5 is important for twitching motility.	May 2020
I18-Microfocus Spectroscopy	Accumulation of ambient phosphate into the periplasm of marine bacteria is proton motive force dependent Nina A. Kamennaya , Kalotina Geraki , David J. Scanlan , Mikhail Zubkov Nature Communications 11 DOI: 10.1038/s41467-020-16428-w Diamond Proposal Number(s): [15802] Open Access Show Abstract ▼ Abstract: Bacteria acquire phosphate (Pi) by maintaining a periplasmic concentration below environmental levels. We recently described an extracellular Pi buffer which appears to counteract the gradient required for Pi diffusion. Here, we demonstrate that various treatments to outer membrane (OM) constituents do not affect the buffered Pi because bacteria accumulate Pi in the periplasm, from which it can be removed hypo-osmotically. The periplasmic Pi can be gradually imported into the cytoplasm by ATP-powered transport, however, the proton motive force (PMF) is not required to keep Pi in the periplasm. In contrast, the accumulation of Pi into the periplasm across the OM is PMF-dependent and can be enhanced by light energy. Because the conventional mechanism of Pi-specific transport cannot explain Pi accumulation in the periplasm we propose that periplasmic Pi anions pair with chemiosmotic cations of the PMF and millions of accumulated Pi pairs could influence the periplasmic osmolarity of marine bacteria.	May 2020
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	CdbA is a DNA-binding protein and c-di-GMP receptor important for nucleoid organization and segregation in Myxococcus xanthus Dorota Skotnicka , Wieland Steinchen , Dobromir Szadkowski , Ian T. Cadby , Andrew L. Lovering , Gert Bange , Lotte Søgaard-andersen Nature Communications 11 DOI: 10.1038/s41467-020-15628-8 Open Access Show Abstract ▼ Abstract: Cyclic di-GMP (c-di-GMP) is a second messenger that modulates multiple responses to environmental and cellular signals in bacteria. Here we identify CdbA, a DNA-binding protein of the ribbon-helix-helix family that binds c-di-GMP in Myxococcus xanthus. CdbA is essential for viability, and its depletion causes defects in chromosome organization and segregation leading to a block in cell division. The protein binds to the M. xanthus genome at multiple sites, with moderate sequence specificity; however, its depletion causes only modest changes in transcription. The interactions of CdbA with c-di-GMP and DNA appear to be mutually exclusive and residue substitutions in CdbA regions important for c-di-GMP binding abolish binding to both c-di-GMP and DNA, rendering these protein variants non-functional in vivo. We propose that CdbA acts as a nucleoid-associated protein that contributes to chromosome organization and is modulated by c-di-GMP, thus revealing a link between c-di-GMP signaling and chromosome biology.	Apr 2020

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