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Open Access
Abstract: The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying the target structural basis, its mutational progression, and the related biological significance to virus replication allows envisaging the development of better-targeted therapies in the context of COVID-19 epidemic and future coronavirus outbreaks. The identification of evolutionary patterns based solely on sequence information analysis for those targets can provide meaningful insights into the molecular basis of host–pathogen interactions and adaptation, leading to drug resistance phenomena. Herein, we will explore how the study of observed and predicted mutations may offer valuable suggestions for the application of the so-called “synthetic lethal” strategy to SARS-CoV-2 Main protease and Spike protein. The synergy between genetics evidence and drug discovery may prioritize the development of novel long-lasting antiviral agents.
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Mar 2023
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Open Access
Abstract: Spectral computed tomography has received considerable interest in recent years since spectral measurements contain much richer information about the object of interest. In spectral computed tomography, we are interested in the energy channel-wise reconstructions of the object. However, such reconstructions suffer from a low signal-to-noise ratio and share the challenges of conventional low-dose computed tomography such as ring artifacts. Ring artifacts arise from errors in the flat fields and can significantly degrade the quality of the reconstruction. We propose an extended flat-field model that exploits high correlation in the spectral flat fields to reduce ring artifacts in channel-wise reconstructions. The extended model relies on the assumption that the spectral flat fields can be well-approximated by a low-rank matrix. Our proposed model works directly on the spectral flat fields and can be combined with any existing reconstruction model, e.g. filtered back projection and iterative methods. The proposed model is validated on a neutron data set. The results show that our method successfully diminishes ring artifacts and improves the quality of the reconstructions. Moreover, the results indicate that our method is robust; it only needs a single spectral flat-field image, whereas existing methods need multiple spectral flat-field images to reach a similar level of ring reduction.
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Mar 2023
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I09-Surface and Interface Structural Analysis
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Diamond Proposal Number(s):
[24219, 31681]
Abstract: Wide bandgap oxide semiconductors have gained significant attention in the fields from flat panel displays to solar cells, but their uses have been limited by the lack of high mobility p-type oxide semiconductors. Recently, β-phase TeO2 has been identified as a promising p-type oxide semiconductor with exceptional device performance. In this Letter, we report on the electronic structure of β-TeO2 studied by a combination of high-resolution x-ray spectroscopy and hybrid density functional theory calculations. The bulk bandgap of β-TeO2 is determined to be 3.7 eV. Direct comparisons between experimental and computational results demonstrate that the top of a valence band (VB) of β-TeO2 is composed of the hybridized Te 5s, Te 5p, and O 2p states, whereas a conduction band (CB) is dominated by unoccupied Te 5p states. The hybridization between spatially dispersive Te 5s2 states and O 2p orbitals helps us to alleviate the strong localization in the VB, leading to small hole effective mass and high hole mobility in β-TeO2. The Te 5p states provide stabilizing effect to the hybridized Te 5s-O 2p states, which is enabled by structural distortions of a β-TeO2 lattice. The multiple advantages of large bandgap, high hole mobility, two-dimensional structure, and excellent stability make β-TeO2 a highly competitive material for next-generation opto-electronic devices.
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Mar 2023
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I22-Small angle scattering & Diffraction
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Diamond Proposal Number(s):
[19127, 18027]
Open Access
Abstract: Hybrid vesicles consisting of phospholipids and block-copolymers are increasingly finding applications in science and technology. Herein, small angle X-ray scattering (SAXS) and cryo-electron tomography (cryo-ET) are used to obtain detailed structural information about hybrid vesicles with different ratios of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and poly(1,2-butadiene-block-ethylene oxide) (PBd22-PEO14, Ms = 1800 g mol−1). Using single particle analysis (SPA) the authors are able to further interpret the information gained from SAXS and cryo-ET experiments, showing that increasing PBd22-PEO14 mole fraction increases the membrane thickness from 52 Å for a pure lipid system to 97 Å for pure PBd22-PEO14 vesicles. Two vesicle populations with different membrane thicknesses in hybrid vesicle samples are found. As these lipids and polymers are reported to homogeneously mix, bistability is inferred between weak and strong interdigitation regimes of PBd22-PEO14 within the hybrid membranes. It is hypothesized that membranes of intermediate structure are not energetically favorable. Therefore, each vesicle exists in one of these two membrane structures, which are assumed to have comparable free energies. The authors conclude that, by combining biophysical methods, accurate determination of the influence of composition on the structural properties of hybrid membranes is achieved, revealing that two distinct membranes structures can coexist in homogeneously mixed lipid-polymer hybrid vesicles.
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Mar 2023
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Krios I-Titan Krios I at Diamond
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David J. K.
Swainsbury
,
Frederick
Hawkings
,
Elizabeth C.
Martin
,
Sabina
Musial
,
Jack H.
Salisbury
,
Philip J.
Jackson
,
David A.
Farmer
,
Matthew P.
Johnson
,
C. Alistair
Siebert
,
Andrew
Hitchcock
,
C. Neil
Hunter
Diamond Proposal Number(s):
[29785]
Open Access
Abstract: Cytochrome bc1 complexes are ubiquinol:cytochrome c oxidoreductases, and as such, they are centrally important components of respiratory and photosynthetic electron transfer chains in many species of bacteria and in mitochondria. The minimal complex has three catalytic components, which are cytochrome b, cytochrome c1, and the Rieske iron–sulfur subunit, but the function of mitochondrial cytochrome bc1 complexes is modified by up to eight supernumerary subunits. The cytochrome bc1 complex from the purple phototrophic bacterium Rhodobacter sphaeroides has a single supernumerary subunit called subunit IV, which is absent from current structures of the complex. In this work we use the styrene–maleic acid copolymer to purify the R. sphaeroides cytochrome bc1 complex in native lipid nanodiscs, which retains the labile subunit IV, annular lipids, and natively bound quinones. The catalytic activity of the four-subunit cytochrome bc1 complex is threefold higher than that of the complex lacking subunit IV. To understand the role of subunit IV, we determined the structure of the four-subunit complex at 2.9 Å using single particle cryogenic electron microscopy. The structure shows the position of the transmembrane domain of subunit IV, which lies across the transmembrane helices of the Rieske and cytochrome c1 subunits. We observe a quinone at the Qo quinone-binding site and show that occupancy of this site is linked to conformational changes in the Rieske head domain during catalysis. Twelve lipids were structurally resolved, making contacts with the Rieske and cytochrome b subunits, with some spanning both of the two monomers that make up the dimeric complex.
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Mar 2023
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B21-High Throughput SAXS
B23-Circular Dichroism
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Alessandro
Paciaroni
,
Valeria
Libera
,
Francesca
Ripanti
,
Andrea
Orecchini
,
Caterina
Petrillo
,
Daniela
Francisci
,
Elisabetta
Schiaroli
,
Samuele
Sabbatini
,
Anna
Gidari
,
Elisa
Bianconi
,
Antonio
Macchiarulo
,
Rohanah
Hussain
,
Lucia
Silvestrini
,
Paolo
Moretti
,
Norhan
Belhaj
,
Matteo
Vercelli
,
Yessica
Roque
,
Paolo
Mariani
,
Lucia
Comez
,
Francesco
Spinozzi
Diamond Proposal Number(s):
[29982, 32331]
Open Access
Abstract: The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruses. Like SARS-CoV and MERS-CoV, the mature and active form of SARS-CoV-2 Mpro is a dimer composed of identical subunits, each with a single active site. Individual monomers, however, have very low or no catalytic activity. As such, inhibition of Mpro can be achieved by molecules that target the substrate binding pocket to block catalytic activity or target the dimerization process. In this study, we investigated GC376, a transition-state analog inhibitor of the main protease of feline infectious peritonitis coronavirus, and Nirmatrelvir (NMV), an oral, bioavailable SARS-CoV-2 Mpro inhibitor with pan-human coronavirus antiviral activity. Our results show that both GC376 and NMV are capable of strongly binding to SARS-CoV-2 Mpro and altering the monomer-dimer equilibrium by stabilizing the dimeric state. This behavior is proposed to be related to a structured hydrogen-bond network established at the Mpro active site, where hydrogen bonds between Ser1’ and Glu166/Phe140 are formed in addition to those achieved by the latter residues with GC376 or NMV.
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Mar 2023
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I15-1-X-ray Pair Distribution Function (XPDF)
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Diamond Proposal Number(s):
[28776]
Abstract: An anion doped aluminium chlorofluoride AlCl0.1F2.8(OTeF5)0.1 (ACF-teflate) was synthesized. The material contains pentafluoroorthotellurate (teflate) groups, which mimic fluoride ions electronically, but are sterically more demanding. They are embedded into the amorphous structure. The latter was studied by PDF analysis, EXAFS data and MAS NMR spectroscopy. The mesoporous powder is a Lewis superacid, and ATR-IR spectra of adsorbed CD3CN reveal a blue-shift of the adsorption band by 73 cm−1, which is larger than the shift for SbF5. Remarkably, ACF-teflate catalyzes dehydrofluorination reactions of monofluoroalkanes to yield olefins in C6D6. In these cases, no Friedel-Crafts products were formed.
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Mar 2023
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[21497]
Open Access
Abstract: Self-assembly of a flexible tritopic aniline and 3-substituted 2-formylpyridine subcomponents around iron(II) templates gave rise to low-spin FeII4L4 capsule, whereas a high-spin FeII3L2 sandwich species formed when a sterically hindered 6-methyl-2-formylpyridine was used. The FeII4L4 cage adopted a new structure type with S4 symmetry, having two mer-Δ and two mer-Ʌ metal vertices, as confirmed by NMR and X-ray crystallographic analysis. The flexibility of the face-capping ligand endows the resulting FeII4L4 framework with conformational plasticity, enabling it to adapt structurally from S4 to T or C3 symmetry upon guest binding. The cage also displayed negative allosteric cooperativity in simultaneously binding different guests within its cavity and at the apertures between its faces.
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Mar 2023
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I03-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[28360]
Abstract: Cystathionine γ-lyase (CGL) is a PLP-dependent enzyme that catalyzes the last step of the reverse transsulfuration route for endogenous cysteine biosynthesis. The canonical CGL-catalyzed process consists of an α,γ-elimination reaction that breaks down cystathionine into cysteine, α-ketobutyrate, and ammonia. In some species, the enzyme can alternatively use cysteine as a substrate, resulting in the production of hydrogen sulfide (H2S). Importantly, inhibition of the enzyme and consequently of its H2S production activity, makes multiresistant bacteria considerably more susceptible to antibiotics. Other organisms, such as Toxoplasma gondii, the causative agent of toxoplasmosis, encode a CGL enzyme (TgCGL) that almost exclusively catalyzes the canonical process, with only minor reactivity to cysteine. Interestingly, the substitution of N360 by a serine (the equivalent amino acid residue in the human enzyme) at the active site changes the specificity of TgCGL for the catalysis of cystathionine, resulting in an enzyme that can cleave both the CγS and the CβS bond of cystathionine. Based on these findings and to deepen the molecular basis underlying the enzyme-substrate specificity, we have elucidated the crystal structures of native TgCGL and the variant TgCGL-N360S from crystals grown in the presence of cystathionine, cysteine, and the inhibitor D,L-propargylglycine (PPG). Our structures reveal the binding mode of each molecule within the catalytic cavity and help explain the inhibitory behavior of cysteine and PPG. A specific inhibitory mechanism of TgCGL by PPG is proposed.
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Mar 2023
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I09-Surface and Interface Structural Analysis
I21-Resonant Inelastic X-ray Scattering (RIXS)
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A. S.
Menon
,
B. J.
Johnston
,
S. G.
Booth
,
L.
Zhang
,
K.
Kress
,
B. E.
Murdock
,
G.
Paez Fajardo
,
N. N.
Anthonisamy
,
N.
Tapia-Ruiz
,
S.
Agrestini
,
M.
Garcia-Fernandez
,
K.
Zhou
,
P. K.
Thakur
,
T. L.
Lee
,
A. J.
Nedoma
,
S. A.
Cussen
,
L. F. J.
Piper
Diamond Proposal Number(s):
[29104, 29113]
Open Access
Abstract: The desire to increase the energy density of stoichiometric layered
Li
TM
O
2
(TM = 3d transition metal) cathode materials has promoted investigation into their properties at high states of charge. Although there is increasing evidence for pronounced oxygen participation in the charge compensation mechanism, questions remain whether this is true
O
-redox, as observed in
Li
-excess cathodes. Through a high-resolution
O
K-edge resonant inelastic x-ray spectroscopy (RIXS) study of the
Mn
-free
Ni
-rich layered oxide
Li
Ni
0.98
W
0.02
O
2
, we demonstrate that the same oxidized oxygen environment exists in both
Li
-excess and non-
Li
-excess systems. The observation of identical RIXS loss features in both classes of compounds is remarkable given the differences in their crystallographic structure and delithiation pathways. This lack of a specific structural motif reveals the importance of electron correlation in the charge compensation mechanism for these systems and indicates how a better description of charge compensation in layered oxides is required to understand anionic redox for energy storage.
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Mar 2023
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