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38 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4 [Next/Last]

Instruments / Technical Area	Publication Details	Published
	A revised partiality model and post-refinement algorithm for X-ray free-electron laser data Helen Ginn , Aaron S. Brewster , Johan Hattne , Gwyndaf Evans , Armin Wagner , Jonathan Grimes , Nicholas K. Sauter , Geoff Sutton , David I. Stuart Acta Crystallographica Section D Biological Crystallography 71, 1400 - 1410 DOI: 10.1107/S1399004715006902 PMID: 26057680 Open Access Show Abstract ▼ Abstract: Research towards using X-ray free-electron laser (XFEL) data to solve structures using experimental phasing methods such as sulfur single-wavelength anomalous dispersion (SAD) has been hampered by shortcomings in the diffraction models for X-ray diffraction from FELs. Owing to errors in the orientation matrix and overly simple partiality models, researchers have required large numbers of images to converge to reliable estimates for the structure-factor amplitudes, which may not be feasible for all biological systems. Here, data for cytoplasmic polyhedrosis virus type 17 (CPV17) collected at 1.3 Å wavelength at the Linac Coherent Light Source (LCLS) are revisited. A previously published definition of a partiality model for reflections illuminated by self-amplified spontaneous emission (SASE) pulses is built upon, which defines a fraction between 0 and 1 based on the intersection of a reflection with a spread of Ewald spheres modelled by a super-Gaussian wavelength distribution in the X-ray beam. A method of post-refinement to refine the parameters of this model is suggested. This has generated a merged data set with an overall discrepancy (by calculating the Rsplit value) of 3.15% to 1.46 Å resolution from a 7225-image data set. The atomic numbers of C, N and O atoms in the structure are distinguishable in the electron-density map. There are 13 S atoms within the 237 residues of CPV17, excluding the initial disordered methionine. These only possess 0.42 anomalous scattering electrons each at 1.3 Å wavelength, but the 12 that have single predominant positions are easily detectable in the anomalous difference Fourier map. It is hoped that these improvements will lead towards XFEL experimental phase determination and structure determination by sulfur SAD and will generally increase the utility of the method for difficult cases.	Jun 2015
I03-Macromolecular Crystallography	A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity Chang Liu , Daming Zhou , Aiste Dijokaite-Guraliuc , Piyada Supasa , Helen M. E. Duyvesteyn , Helen M. Ginn , Muneeswaran Selvaraj , Alexander J. Mentzer , Raksha Das , Thushan I. De Silva , Thomas G. Ritter , Megan Plowright , Thomas A.h. Newman , Lizzie Stafford , Barbara Kronsteiner , Nigel Temperton , Yuan Lui , Martin Fellermeyer , Philip Goulder , Paul Klenerman , Susanna J. Dunachie , Michael I. Barton , Mikhail A. Kutuzov , Omer Dushek , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Reports Medicine 376 DOI: 10.1016/j.xcrm.2024.101553 Diamond Proposal Number(s): [28534, 27009] Open Access Show Abstract ▼ Abstract: BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.	May 2024
	An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data Tamar Mehlman , Helen M. Ginn , Daniel A. Keedy Structure 65 DOI: 10.1016/j.str.2024.05.010 Open Access Show Abstract ▼ Abstract: Due to their low binding affinities, detecting small-molecule fragments bound to protein structures from crystallographic datasets has been a challenge. Here, we report a trove of 65 new fragment hits for PTP1B, an “undruggable” therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (∼50% more) “hidden” ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.	Jun 2024
I24-Microfocus Macromolecular Crystallography	An ultraviolet-driven rescue pathway for oxidative stress to eye lens protein human gamma-D crystallin Jake A. Hill , Yvonne Nyathi , Sam Horrell , David Von Stetten , Danny Axford , Robin L. Owen , Godfrey S. Beddard , Arwen R. Pearson , Helen M. Ginn , Briony Yorke Communications Chemistry 7 DOI: 10.1038/s42004-024-01163-w Diamond Proposal Number(s): [27314] Open Access Show Abstract ▼ Abstract: Human gamma-D crystallin (HGD) is a major constituent of the eye lens. Aggregation of HGD contributes to cataract formation, the leading cause of blindness worldwide. It is unique in its longevity, maintaining its folded and soluble state for 50-60 years. One outstanding question is the structural basis of this longevity despite oxidative aging and environmental stressors including ultraviolet radiation (UV). Here we present crystallographic structures evidencing a UV-induced crystallin redox switch mechanism. The room-temperature serial synchrotron crystallographic (SSX) structure of freshly prepared crystallin mutant (R36S) shows no post-translational modifications. After aging for nine months in the absence of light, a thiol-adduct (dithiothreitol) modifying surface cysteines is observed by low-dose SSX. This is shown to be UV-labile in an acutely light-exposed structure. This suggests a mechanism by which a major source of crystallin damage, UV, may also act as a rescuing factor in a finely balanced redox system.	Apr 2024
I03-Macromolecular Crystallography	Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum Aekkachai Tuekprakhon , Jiandong Huo , Rungtiwa Nutalai , Aiste Dijokaite-Guraliuc , Daming Zhou , Helen M. Ginn , Muneeswaran Selvaraj , Chang Liu , Alexander J. Mentzer , Piyada Supasa , Helen M. E. Duyvesteyn , Raksha Das , Donal Skelly , Thomas G. Ritter , Ali Amini , Sagida Bibi , Sandra Adele , Sile Ann Johnson , Bede Constantinides , Hermione Webster , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Derrick Crook , Andrew J. Pollard , Teresa Lambe , Philip Goulder , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton , Christopher Conlon , Alexandra Deeks , John Frater , Lisa Frending , Siobhan Gardiner , Anni Jämsén , Katie Jeffery , Tom Malone , Eloise Phillips , Lucy Rothwell , Lizzie Stafford Cell DOI: 10.1016/j.cell.2022.06.005 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: The Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa’s Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.	Jun 2022
I03-Macromolecular Crystallography	Antibody evasion by the P.1 strain of SARS-CoV-2 Wanwisa Dejnirattisai , Daming Zhou , Piyada Supasa , Chang Liu , Alexander J. Mentzer , Helen M. Ginn , Yuguang Zhao , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Guido Paesen , César López-Camacho , Jose Slon-Campos , Thomas S. Walter , Donal Skelly , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola C. Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Christina Dold , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah Gilbert , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Neil G. Paterson , Mark A. Williams , David R. Hall , Ruben J. G. Hulswit , Thomas A. Bowden , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.03.055 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.	Mar 2021
	Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease Vasundara Srinivasan , Hévila Brognaro , Prince R. Prabhu , Edmarcia Elisa De Souza , Sebastian Günther , Patrick Y. A. Reinke , Thomas J. Lane , Helen Ginn , Huijong Han , Wiebke Ewert , Janina Sprenger , Faisal H. M. Koua , Sven Falke , Nadine Werner , Hina Andaleeb , Najeeb Ullah , Bruno Alves Franca , Mengying Wang , Angélica Luana C. Barra , Markus Perbandt , Martin Schwinzer , Christina Schmidt , Lea Brings , Kristina Lorenzen , Robin Schubert , Rafael Rahal Guaragna Machado , Erika Donizette Candido , Danielle Bruna Leal Oliveira , Edison Luiz Durigon , Stephan Niebling , Angelica Struve Garcia , Oleksandr Yefanov , Julia Lieske , Luca Gelisio , Martin Domaracky , Philipp Middendorf , Michael Groessler , Fabian Trost , Marina Galchenkova , Aida Rahmani Mashhour , Sofiane Saouane , Johanna Hakanpää , Markus Wolf , Maria Garcia Alai , Dusan Turk , Arwen R. Pearson , Henry N. Chapman , Winfried Hinrichs , Carsten Wrenger , Alke Meents , Christian Betzel Communications Biology 5 DOI: 10.1038/s42003-022-03737-7 Open Access Show Abstract ▼ Abstract: SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host’s innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.	Aug 2022
I03-Macromolecular Crystallography	Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera Daming Zhou , Wanwisa Dejnirattisai , Piyada Supasa , Chang Liu , Alexander J. Mentzer , Helen M. Ginn , Yuguang Zhao , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Guido C. Paesen , Cesar Lopez-Camacho , Jose Slon-Campos , Bassam Hallis , Naomi Coombes , Kevin Bewley , Sue Charlton , Thomas S. Walter , Donal Skelly , Sheila F. Lumley , Christina Dold , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah Gilbert , William James , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Elizabeth E. Fry , Juthathip Mongkolspaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.02.037 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: The race to produce vaccines against SARS-CoV-2 began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK–B.1.1.7, South Africa–B.1.351 and Brazil–P.1. These variants have multiple changes in the immunodominant spike protein which facilitates viral cell entry via the Angiotensin converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K although K417N and N501Y act together against some important antibody classes. In a number of cases it would appear that convalescent and some vaccine serum offers limited protection against this variant.	Feb 2021
	Femtosecond X-ray coherent diffraction of aligned amyloid fibrils on low background graphene Carolin Seuring , Kartik Ayyer , Eleftheria Filippaki , Miriam Barthelmess , Jean-Nicolas Longchamp , Philippe Ringler , Tommaso Pardini , David H. Wojtas , Matthew A. Coleman , Katerina Dörner , Silje Fuglerud , Greger Hammarin , Birgit Habenstein , Annette E. Langkilde , Antoine Loquet , Alke Meents , Roland Riek , Henning Stahlberg , Sébastien Boutet , Mark S. Hunter , Jason Koglin , Mengning Liang , Helen M. Ginn , Rick P. Millane , Matthias Frank , Anton Barty , Henry N. Chapman Nature Communications 9 DOI: 10.1038/s41467-018-04116-9 Open Access Show Abstract ▼ Abstract: Here we present a new approach to diffraction imaging of amyloid fibrils, combining a free-standing graphene support and single nanofocused X-ray pulses of femtosecond duration from an X-ray free-electron laser. Due to the very low background scattering from the graphene support and mutual alignment of filaments, diffraction from tobacco mosaic virus (TMV) filaments and amyloid protofibrils is obtained to 2.7 Å and 2.4 Å resolution in single diffraction patterns, respectively. Some TMV diffraction patterns exhibit asymmetry that indicates the presence of a limited number of axial rotations in the XFEL focus. Signal-to-noise levels from individual diffraction patterns are enhanced using computational alignment and merging, giving patterns that are superior to those obtainable from synchrotron radiation sources. We anticipate that our approach will be a starting point for further investigations into unsolved structures of filaments and other weakly scattering objects.	May 2018
Detectors	Fixed target combined with spectral mapping: approaching 100% hit rates for serial crystallography Saeed Oghbaey , Antoine Sarracini , Helen M. Ginn , Olivier Pare-Labrosse , Anling Kuo , Alexander Marx , Sascha W. Epp , Darren A. Sherrell , Bryan T. Eger , Yinpeng Zhong , Rolf Loch , Valerio Mariani , Roberto Alonso-Mori , Silke Nelson , Henrik T. Lemke , Robin L. Owen , Arwen R. Pearson , David I. Stuart , Oliver P. Ernst , Henrike Mueller-Werkmeister , R. J. Dwayne Miller Acta Crystallographica Section D Structural Biology 72, 944 - 955 DOI: 10.1107/S2059798316010834 Show Abstract ▼ Abstract: The advent of ultrafast highly brilliant coherent X-ray free-electron laser sources has driven the development of novel structure-determination approaches for proteins, and promises visualization of protein dynamics on sub-picosecond timescales with full atomic resolution. Significant efforts are being applied to the development of sample-delivery systems that allow these unique sources to be most efficiently exploited for high-throughput serial femtosecond crystallography. Here, the next iteration of a fixed-target crystallography chip designed for rapid and reliable delivery of up to 11 259 protein crystals with high spatial precision is presented. An experimental scheme for predetermining the positions of crystals in the chip by means of in situ spectroscopy using a fiducial system for rapid, precise alignment and registration of the crystal positions is presented. This delivers unprecedented performance in serial crystallography experiments at room temperature under atmospheric pressure, giving a raw hit rate approaching 100% with an effective indexing rate of approximately 50%, increasing the efficiency of beam usage and allowing the method to be applied to systems where the number of crystals is limited.	Aug 2016

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