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18 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I22-Small angle scattering & Diffraction	Characterisation of a synthetic Archeal membrane reveals a possible new adaptation route to extreme conditions Marta Salvador-Castell , Maksym Golub , Nelli Erwin , Bruno Deme , Nicholas J. Brooks , Roland Winter , Judith Peters , Philippe Oger Communications Biology 4 DOI: 10.1038/s42003-021-02178-y Diamond Proposal Number(s): [23722] Open Access Show Abstract ▼ Abstract: It has been proposed that adaptation to high temperature involved the synthesis of monolayer-forming ether phospholipids. Recently, a novel membrane architecture was proposed to explain the membrane stability in polyextremophiles unable to synthesize such lipids, in which apolar polyisoprenoids populate the bilayer midplane and modify its physico-chemistry, extending its stability domain. Here, we have studied the effect of the apolar polyisoprenoid squalane on a model membrane analogue using neutron diffraction, SAXS and fluorescence spectroscopy. We show that squalane resides inside the bilayer midplane, extends its stability domain, reduces its permeability to protons but increases that of water, and induces a negative curvature in the membrane, allowing the transition to novel non-lamellar phases. This membrane architecture can be transposed to early membranes and could help explain their emergence and temperature tolerance if life originated near hydrothermal vents. Transposed to the archaeal bilayer, this membrane architecture could explain the tolerance to high temperature in hyperthermophiles which grow at temperatures over 100 °C while having a membrane bilayer. The induction of a negative curvature to the membrane could also facilitate crucial cell functions that require high bending membranes.	Jun 2021
Krios II-Titan Krios II at Diamond	3D architecture and structural flexibility revealed in the subfamily of large glutamate dehydrogenases by a mycobacterial enzyme Melisa Lazaro , Roberto Melero , Charlotte Huet , Jorge Lopez-Alonso , Sandra Delgado , Alexandra Dodu , Eduardo M. Bruch , Luciano A. Abriata , Pedro M. Alzari , Mikel Valle , María-Natalia Lisa Communications Biology 4 DOI: 10.1038/s42003-021-02222-x Diamond Proposal Number(s): [14743] Open Access Show Abstract ▼ Abstract: Glutamate dehydrogenases (GDHs) are widespread metabolic enzymes that play key roles in nitrogen homeostasis. Large glutamate dehydrogenases composed of 180 kDa subunits (L-GDHs180) contain long N- and C-terminal segments flanking the catalytic core. Despite the relevance of L-GDHs180 in bacterial physiology, the lack of structural data for these enzymes has limited the progress of functional studies. Here we show that the mycobacterial L-GDH180 (mL-GDH180) adopts a quaternary structure that is radically different from that of related low molecular weight enzymes. Intersubunit contacts in mL-GDH180 involve a C-terminal domain that we propose as a new fold and a flexible N-terminal segment comprising ACT-like and PAS-type domains that could act as metabolic sensors for allosteric regulation. These findings uncover unique aspects of the structure-function relationship in the subfamily of L-GDHs.	Jun 2021
Krios I-Titan Krios I at Diamond	Structure and lipid dynamics in the maintenance of lipid asymmetry inner membrane complex of A. baumannii Daniel Mann , Junping Fan , Kamolrat Somboon , Daniel P. Farrell , Andrew Muenks , Svetomir B. Tzokov , Frank Dimaio , Syma Khalid , Samuel I. Miller , Julien R. C. Bergeron Communications Biology 4 DOI: 10.1038/s42003-021-02318-4 Diamond Proposal Number(s): [19832] Open Access Show Abstract ▼ Abstract: Multi-resistant bacteria are a major threat in modern medicine. The gram-negative coccobacillus Acinetobacter baumannii currently leads the WHO list of pathogens in critical need for new therapeutic development. The maintenance of lipid asymmetry (MLA) protein complex is one of the core machineries that transport lipids from/to the outer membrane in gram-negative bacteria. It also contributes to broad-range antibiotic resistance in several pathogens, most prominently in A. baumannii. Nonetheless, the molecular details of its role in lipid transport has remained largely elusive. Here, we report the cryo-EM maps of the core MLA complex, MlaBDEF, from the pathogen A. baumannii, in the apo-, ATP- and ADP-bound states, revealing multiple lipid binding sites in the cytosolic and periplasmic side of the complex. Molecular dynamics simulations suggest their potential trajectory across the membrane. Collectively with the recently-reported structures of the E. coli orthologue, this data also allows us to propose a molecular mechanism of lipid transport by the MLA system.	Jun 2021
I03-Macromolecular Crystallography	SWI/SNF subunit BAF155 N-terminus structure informs the impact of cancer-associated mutations and reveals a potential drug binding site Mark D. Allen , Stefan M. V. Freund , Mark Bycroft , Giovanna Zinzalla Communications Biology 4 DOI: 10.1038/s42003-021-02050-z Open Access Show Abstract ▼ Abstract: SWI/SNF (BAF) chromatin remodelling complexes are key regulators of gene expression programs, and attractive drug targets for cancer therapies. Here we show that the N-terminus of the BAF155/SMARCC1 subunit contains a putative DNA-binding MarR-like domain, a chromodomain and a BRCT domain that are interconnected to each other to form a distinct module. In this structure the chromodomain makes interdomain interactions and has lost its canonical function to bind to methylated lysines. The structure provides new insights into the missense mutations that target this module in cancer. This study also reveals two adjacent, highly-conserved pockets in a cleft between the domains that form a potential binding site, which can be targeted with small molecules, offering a new strategy to target SWI/SNF complexes.	May 2021
Krios I-Titan Krios I at Diamond Krios II-Titan Krios II at Diamond Krios III-Titan Krios III at Diamond	CryoET structures of immature HIV Gag reveal six-helix bundle Luiza Mendonca , Dapeng Sun , Jiying Ning , Jiwei Liu , Abhay Kotecha , Mateusz Olek , Thomas Frosio , Xiaofeng Fu , Benjamin A. Himes , Alex B. Kleinpeter , Eric O. Freed , Jing Zhou , Christopher Aiken , Peijun Zhang Communications Biology 4 DOI: 10.1038/s42003-021-01999-1 Diamond Proposal Number(s): [18477, 21005, 21004] Open Access Show Abstract ▼ Abstract: Gag is the HIV structural precursor protein which is cleaved by viral protease to produce mature infectious viruses. Gag is a polyprotein composed of MA (matrix), CA (capsid), SP1, NC (nucleocapsid), SP2 and p6 domains. SP1, together with the last eight residues of CA, have been hypothesized to form a six-helix bundle responsible for the higher-order multimerization of Gag necessary for HIV particle assembly. However, the structure of the complete six-helix bundle has been elusive. Here, we determined the structures of both Gag in vitro assemblies and Gag viral-like particles (VLPs) to 4.2 Å and 4.5 Å resolutions using cryo-electron tomography and subtomogram averaging by emClarity. A single amino acid mutation (T8I) in SP1 stabilizes the six-helix bundle, allowing to discern the entire CA-SP1 helix connecting to the NC domain. These structures provide a blueprint for future development of small molecule inhibitors that can lock SP1 in a stable helical conformation, interfere with virus maturation, and thus block HIV-1 infection.	Apr 2021
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	The structure of a major surface antigen SAG19 from Eimeria tenella unifies the Eimeria SAG family Nur Zazarina Ramly , Samuel R. Dix , Sergey N. Ruzheinikov , Svetlana E. Sedelnikova , Patrick J. Baker , Yock-Ping Chow , Fiona M. Tomley , Damer P. Blake , Kiew-Lian Wan , Sheila Nathan , David W. Rice Communications Biology 4 DOI: 10.1038/s42003-021-01904-w Diamond Proposal Number(s): [1218, 24447] Open Access Show Abstract ▼ Abstract: In infections by apicomplexan parasites including Plasmodium, Toxoplasma gondii, and Eimeria, host interactions are mediated by proteins including families of membrane-anchored cysteine-rich surface antigens (SAGs) and SAG-related sequences (SRS). Eimeria tenella causes caecal coccidiosis in chickens and has a SAG family with over 80 members making up 1% of the proteome. We have solved the structure of a representative E. tenella SAG, EtSAG19, revealing that, despite a low level of sequence similarity, the entire Eimeria SAG family is unified by its three-layer αβα fold which is related to that of the CAP superfamily. Furthermore, sequence comparisons show that the Eimeria SAG fold is conserved in surface antigens of the human coccidial parasite Cyclospora cayetanensis but this fold is unrelated to that of the SAGs/SRS proteins expressed in other apicomplexans including Plasmodium species and the cyst-forming coccidia Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti. However, despite having very different structures, Consurf analysis showed that Eimeria SAG and Toxoplasma SRS families each exhibit marked hotspots of sequence hypervariability that map to their surfaces distal to the membrane anchor. This suggests that the primary and convergent purpose of the different structures is to provide a platform onto which sequence variability can be imposed.	Mar 2021
	Structure and dynamics of the E. coli chemotaxis core signaling complex by cryo-electron tomography and molecular simulations C. Keith Cassidy , Benjamin A. Himes , Dapeng Sun , Jun Ma , Gongpu Zhao , John S. Parkinson , Phillip J. Stansfeld , Zaida Luthey-Schulten , Peijun Zhang Communications Biology 3 DOI: 10.1038/s42003-019-0748-0 Show Abstract ▼ Abstract: To enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU). Despite decades of study, important questions surrounding the molecular mechanisms of sensory signal transduction remain unresolved, owing especially to the lack of a high-resolution CSU structure. Here, we use cryo-electron tomography and sub-tomogram averaging to determine a structure of the Escherichia coli CSU at sub-nanometer resolution. Based on our experimental data, we use molecular simulations to construct an atomistic model of the CSU, enabling a detailed characterization of CheA conformational dynamics in its native structural context. We identify multiple, distinct conformations of the critical P4 domain as well as asymmetries in the localization of the P3 bundle, offering several novel insights into the CheA signaling mechanism.	Dec 2020
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Caffeine inhibits Notum activity by binding at the catalytic pocket Yuguang Zhao , Jingshan Ren , James Hillier , Weixian Lu , Edith Yvonne Jones Communications Biology 3 DOI: 10.1038/s42003-020-01286-5 Diamond Proposal Number(s): [14744] Open Access Show Abstract ▼ Abstract: Notum inhibits Wnt signalling via enzymatic delipidation of Wnt ligands. Restoration of Wnt signalling by small molecule inhibition of Notum may be of therapeutic benefit in a number of pathologies including Alzheimer’s disease. Here we report Notum activity can be inhibited by caffeine (IC50 19 µM), but not by demethylated caffeine metabolites: paraxanthine, theobromine and theophylline. Cellular luciferase assays show Notum-suppressed Wnt3a function can be restored by caffeine with an EC50 of 46 µM. The dissociation constant (Kd) between Notum and caffeine is 85 µM as measured by surface plasmon resonance. High-resolution crystal structures of Notum complexes with caffeine and its minor metabolite theophylline show both compounds bind at the centre of the enzymatic pocket, overlapping the position of the natural substrate palmitoleic lipid, but using different binding modes. The structural information reported here may be of relevance for the design of more potent brain-accessible Notum inhibitors.	Oct 2020
I03-Macromolecular Crystallography	Structural effects of the highly protective V127 polymorphism on human prion protein Laszlo L. P. Hosszu , Rebecca Conners , Daljit Sangar , Mark Batchelor , Elizabeth B. Sawyer , Stuart Fisher , Matthew J. Cliff , Andrea M. Hounslow , Katherine Mcauley , R. Leo Brady , Graham S. Jackson , Jan Bieschke , Jonathan P. Waltho , John Collinge Communications Biology 3 DOI: 10.1038/s42003-020-01126-6 Diamond Proposal Number(s): [4923, 5969] Open Access Show Abstract ▼ Abstract: Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). A single point mutation (G127V) in human PrP prevents prion disease, however the structural basis for its protective effect remains unknown. Here we show that the mutation alters and constrains the PrP backbone conformation preceding the PrP β-sheet, stabilising PrP dimer interactions by increasing intermolecular hydrogen bonding. It also markedly changes the solution dynamics of the β2-α2 loop, a region of PrP structure implicated in prion transmission and cross-species susceptibility. Both of these structural changes may affect access to protein conformers susceptible to prion formation and explain its profound effect on prion disease.	Jul 2020
I04-Macromolecular Crystallography	Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy Varunya Chantadul , Gareth S. A. Wright , Kangsa Amporndanai , Munazza Shahid , Svetlana V. Antonyuk , Gina Washbourn , Michael Rogers , Natalie Roberts , Matthew Pye , Paul M. O’neill , S. Samar Hasnain Communications Biology 3 DOI: 10.1038/s42003-020-0826-3 Diamond Proposal Number(s): [15991, 21970] Open Access Show Abstract ▼ Abstract: Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template.	Mar 2020

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