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875 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
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A single sulfatase is required to access colonic mucin by a gut bacterium Ana S. Luis , Chunsheng Jin , Gabriel Vasconcelos Pereira , Robert W. P. Glowacki , Sadie R. Gugel , Shaleni Singh , Dominic P. Byrne , Nicholas A. Pudlo , James A. London , Arnaud Basle , Mark Reihill , Stefan Oscarson , Patrick A. Eyers , Mirjam Czjzek , Gurvan Michel , Tristan Barbeyron , Edwin A. Yates , Gunnar C. Hansson , Niclas G. Karlsson , Alan Cartmell , Eric C. Martens Nature 105 DOI: 10.1038/s41586-021-03967-5 Diamond Proposal Number(s): [18598] Open Access Show Abstract ▼ Abstract: Humans have co-evolved with a dense community of microbial symbionts that inhabit the lower intestine. In the colon, secreted mucus creates a barrier that separates these microorganisms from the intestinal epithelium. Some gut bacteria are able to utilize mucin glycoproteins, the main mucus component, as a nutrient source. However, it remains unclear which bacterial enzymes initiate degradation of the complex O-glycans found in mucins. In the distal colon, these glycans are heavily sulfated, but specific sulfatases that are active on colonic mucins have not been identified. Here we show that sulfatases are essential to the utilization of distal colonic mucin O-glycans by the human gut symbiont Bacteroides thetaiotaomicron. We characterized the activity of 12 different sulfatases produced by this species, showing that they are collectively active on all known sulfate linkages in O-glycans. Crystal structures of three enzymes provide mechanistic insight into the molecular basis of substrate specificity. Unexpectedly, we found that a single sulfatase is essential for utilization of sulfated O-glycans in vitro and also has a major role in vivo. Our results provide insight into the mechanisms of mucin degradation by a prominent group of gut bacteria, an important process for both normal microbial gut colonization and diseases such as inflammatory bowel disease.	Oct 2021
I03-Macromolecular Crystallography	Higher-order phosphatase–substrate contacts terminate the integrated stress response Yahui Yan , Heather P. Harding , David Ron Nature Structural & Molecular Biology 28, 835 - 846 DOI: 10.1038/s41594-021-00666-7 Diamond Proposal Number(s): [21426] Open Access Show Abstract ▼ Abstract: Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c–PPP1R15A–G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.	Oct 2021
Krios I-Titan Krios I at Diamond Krios II-Titan Krios II at Diamond	Structural basis of soluble membrane attack complex packaging for clearance Anais Menny , Marie V. Lukassen , Emma C. Couves , Vojtech Franc , Albert J. R. Heck , Doryen Bubeck Nature Communications 12 DOI: 10.1038/s41467-021-26366-w Diamond Proposal Number(s): [18659] Open Access Show Abstract ▼ Abstract: Unregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease. To prevent bystander damage during an immune response, extracellular chaperones (clusterin and vitronectin) capture and clear soluble precursors to the membrane attack complex (sMAC). However, how these chaperones block further polymerization of MAC and prevent the complex from binding target membranes remains unclear. Here, we address that question by combining cryo electron microscopy (cryoEM) and cross-linking mass spectrometry (XL-MS) to solve the structure of sMAC. Together our data reveal how clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC. Furthermore, we show that the pore-forming C9 protein is trapped in an intermediate conformation whereby only one of its two transmembrane β-hairpins has unfurled. This structure provides molecular details for immune pore formation and helps explain a complement control mechanism that has potential implications for how cell clearance pathways mediate immune homeostasis.	Oct 2021
Krios I-Titan Krios I at Diamond	Unwinding of a DNA replication fork by a hexameric viral helicase Abid Javed , Balazs Major , Jonathan A. Stead , Cyril M. Sanders , Elena V. Orlova Nature Communications 12 DOI: 10.1038/s41467-021-25843-6 Diamond Proposal Number(s): [14704] Open Access Show Abstract ▼ Abstract: Hexameric helicases are motor proteins that unwind double-stranded DNA (dsDNA) during DNA replication but how they are optimised for strand separation is unclear. Here we present the cryo-EM structure of the full-length E1 helicase from papillomavirus, revealing all arms of a bound DNA replication fork and their interactions with the helicase. The replication fork junction is located at the entrance to the helicase collar ring, that sits above the AAA + motor assembly. dsDNA is escorted to and the 5´ single-stranded DNA (ssDNA) away from the unwinding point by the E1 dsDNA origin binding domains. The 3´ ssDNA interacts with six spirally-arranged β-hairpins and their cyclical top-to-bottom movement pulls the ssDNA through the helicase. Pulling of the RF against the collar ring separates the base-pairs, while modelling of the conformational cycle suggest an accompanying movement of the collar ring has an auxiliary role, helping to make efficient use of ATP in duplex unwinding.	Sep 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure of a Ty1 restriction factor reveals the molecular basis of transposition copy number control Matthew A. Cottee , Sean L. Beckwith , Suzanne C. Letham , Sarah J. Kim , George R. Young , Jonathan P. Stoye , David J. Garfinkel , Ian A. Taylor Nature Communications 12 DOI: 10.1038/s41467-021-25849-0 Diamond Proposal Number(s): [13775] Open Access Show Abstract ▼ Abstract: Excessive replication of Saccharomyces cerevisiae Ty1 retrotransposons is regulated by Copy Number Control, a process requiring the p22/p18 protein produced from a sub-genomic transcript initiated within Ty1 GAG. In retrotransposition, Gag performs the capsid functions required for replication and re-integration. To minimize genomic damage, p22/p18 interrupts virus-like particle function by interaction with Gag. Here, we present structural, biophysical and genetic analyses of p18m, a minimal fragment of Gag that restricts transposition. The 2.8 Å crystal structure of p18m reveals an all α-helical protein related to mammalian and insect ARC proteins. p18m retains the capacity to dimerise in solution and the crystal structures reveal two exclusive dimer interfaces. We probe our findings through biophysical analysis of interface mutants as well as Ty1 transposition and p18m restriction in vivo. Our data provide insight into Ty1 Gag structure and suggest how p22/p18 might function in restriction through a blocking-of-assembly mechanism.	Sep 2021
Krios III-Titan Krios III at Diamond Krios IV-Titan Krios IV at Diamond	Structural basis of RNA polymerase inhibition by viral and host factors Simona Pilotto , Thomas Fouqueau , Natalya Lukoyanova , Carol Sheppard , Soizick Lucas-Staat , Luis Miguel Diaz-Santin , Dorota Matelska , David Prangishvili , Alan C. M. Cheung , Finn Werner Nature Communications 12 DOI: 10.1038/s41467-021-25666-5 Diamond Proposal Number(s): [20287] Open Access Show Abstract ▼ Abstract: RNA polymerase inhibition plays an important role in the regulation of transcription in response to environmental changes and in the virus-host relationship. Here we present the high-resolution structures of two such RNAP-inhibitor complexes that provide the structural bases underlying RNAP inhibition in archaea. The Acidianus two-tailed virus encodes the RIP factor that binds inside the DNA-binding channel of RNAP, inhibiting transcription by occlusion of binding sites for nucleic acid and the transcription initiation factor TFB. Infection with the Sulfolobus Turreted Icosahedral Virus induces the expression of the host factor TFS4, which binds in the RNAP funnel similarly to eukaryotic transcript cleavage factors. However, TFS4 allosterically induces a widening of the DNA-binding channel which disrupts trigger loop and bridge helix motifs. Importantly, the conformational changes induced by TFS4 are closely related to inactivated states of RNAP in other domains of life indicating a deep evolutionary conservation of allosteric RNAP inhibition.	Sep 2021
I11-High Resolution Powder Diffraction	Element selection for crystalline inorganic solid discovery guided by unsupervised machine learning of experimentally explored chemistry Andrij Vasylenko , Jacinthe Gamon , Benjamin B. Duff , Vladimir V. Gusev , Luke M. Daniels , Marco Zanella , J. Felix Shin , Paul M. Sharp , Alexandra Morscher , Ruiyong Chen , Alex R. Neale , Laurence J. Hardwick , John B. Claridge , Frédéric Blanc , Michael W. Gaultois , Matthew S. Dyer , Matthew J. Rosseinsky Nature Communications 12 DOI: 10.1038/s41467-021-25343-7 Diamond Proposal Number(s): [23666] Open Access Show Abstract ▼ Abstract: The selection of the elements to combine delimits the possible outcomes of synthetic chemistry because it determines the range of compositions and structures, and thus properties, that can arise. For example, in the solid state, the elemental components of a phase field will determine the likelihood of finding a new crystalline material. Researchers make these choices based on their understanding of chemical structure and bonding. Extensive data are available on those element combinations that produce synthetically isolable materials, but it is difficult to assimilate the scale of this information to guide selection from the diversity of potential new chemistries. Here, we show that unsupervised machine learning captures the complex patterns of similarity between element combinations that afford reported crystalline inorganic materials. This model guides prioritisation of quaternary phase fields containing two anions for synthetic exploration to identify lithium solid electrolytes in a collaborative workflow that leads to the discovery of Li3.3SnS3.3Cl0.7. The interstitial site occupancy combination in this defect stuffed wurtzite enables a low-barrier ion transport pathway in hexagonal close-packing.	Sep 2021
I04-Macromolecular Crystallography	Auxiliary interfaces support the evolution of specific toxin–antitoxin pairing Grzegorz J. Grabe , Rachel T. Giorgio , Alexander M. J. Hall , Rhodri M. L. Morgan , Laurent Dubois , Tyler A. Sisley , Julian A. Rycroft , Stephen A. Hare , Sophie Helaine Nature Chemical Biology 163 DOI: 10.1038/s41589-021-00862-y Diamond Proposal Number(s): [17221] Show Abstract ▼ Abstract: Toxin–antitoxin (TA) systems are a large family of genes implicated in the regulation of bacterial growth and its arrest in response to attacks. These systems encode nonsecreted toxins and antitoxins that specifically pair, even when present in several paralogous copies per genome. Salmonella enterica serovar Typhimurium contains three paralogous TacAT systems that block bacterial translation. We determined the crystal structures of the three TacAT complexes to understand the structural basis of specific TA neutralization and the evolution of such specific pairing. In the present study, we show that alteration of a discrete structural add-on element on the toxin drives specific recognition by their cognate antitoxin underpinning insulation of the three pairs. Similar to other TA families, the region supporting TA-specific pairing is key to neutralization. Our work reveals that additional TA interfaces beside the main neutralization interface increase the safe space for evolution of pairing specificity.	Sep 2021
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Molecular mechanism of sugar transport in plants unveiled by structures of glucose/H+ symporter STP10 Laust Bavnhøj , Peter Aasted Paulsen , Jose C. Flores-Canales , Birgit Schiøtt , Bjorn Panyella Pedersen Nature Plants 4 DOI: 10.1038/s41477-021-00992-0 Diamond Proposal Number(s): [23316, 17844] Show Abstract ▼ Abstract: Sugars are essential sources of energy and carbon and also function as key signalling molecules in plants. Sugar transport proteins (STP) are proton-coupled symporters responsible for uptake of glucose from the apoplast into plant cells. They are integral to organ development in symplastically isolated tissues such as seed, pollen and fruit. Additionally, STPs play a vital role in plant responses to stressors such as dehydration and prevalent fungal infections like rust and mildew. Here we present a structure of Arabidopsis thaliana STP10 in the inward-open conformation at 2.6 Å resolution and a structure of the outward-occluded conformation at improved 1.8 Å resolution, both with glucose and protons bound. The two structures describe key states in the STP transport cycle. Together with molecular dynamics simulations that establish protonation states and biochemical analysis, they pinpoint structural elements, conserved in all STPs, that clarify the basis of proton-to-glucose coupling. These results advance our understanding of monosaccharide uptake, which is essential for plant organ development, and set the stage for bioengineering strategies in crops.	Sep 2021
Krios II-Titan Krios II at Diamond	A CDK-regulated chromatin segregase promoting chromosome replication Erika Chacin , Priyanka Bansal , Karl-Uwe Reusswig , Luis M. Diaz-Santin , Pedro Ortega , Petra Vizjak , Belen Gomez-Gonzalez , Felix Müller-Planitz , Andrés Aguilera , Boris Pfander , Alan C. M. Cheung , Christoph F. Kurat Nature Communications 12 DOI: 10.1038/s41467-021-25424-7 Diamond Proposal Number(s): [20287] Open Access Show Abstract ▼ Abstract: The replication of chromosomes during S phase is critical for cellular and organismal function. Replicative stress can result in genome instability, which is a major driver of cancer. Yet how chromatin is made accessible during eukaryotic DNA synthesis is poorly understood. Here, we report the characterization of a chromatin remodeling enzyme—Yta7—entirely distinct from classical SNF2-ATPase family remodelers. Yta7 is a AAA+ -ATPase that assembles into ~1 MDa hexameric complexes capable of segregating histones from DNA. The Yta7 chromatin segregase promotes chromosome replication both in vivo and in vitro. Biochemical reconstitution experiments using purified proteins revealed that the enzymatic activity of Yta7 is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK). S-CDK phosphorylation stimulates ATP hydrolysis by Yta7, promoting nucleosome disassembly and chromatin replication. Our results present a mechanism for how cells orchestrate chromatin dynamics in co-ordination with the cell cycle machinery to promote genome duplication during S phase.	Sep 2021

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