I04-Macromolecular Crystallography
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Stéphane
Bourg
,
Matthieu
Place
,
Chloé
Copin
,
Apirat
Chaikuad
,
Thomas
Robert
,
Hanna
Holzmann
,
Susanne
Müller
,
Stéphane
Bach
,
Sandrine
Ruchaud
,
Stefan
Knapp
,
Frédéric
Buron
,
Sylvain
Routier
,
Pascal
Bonnet
Open Access
Abstract: CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer’s disease and other diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.
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Oct 2026
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I11-High Resolution Powder Diffraction
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Diamond Proposal Number(s):
[36314]
Open Access
Abstract: Ocean-bearing icy worlds may harbour the necessary conditions for life, but we do not yet understand the processes that deliver ocean fluids to the surface where they are accessible to spacecraft. We demonstrate that hydrates of sodium-chloride (NaCl), a constituent of icy world oceans, record the thermal conditions experienced by NaCl rich fluids as they freeze. Through laboratory experiments, we identify four distinct NaCl-H2O assemblages, comprising crystalline and amorphous phases. The specific phase assemblage produced by freezing of brine depends on both the cooling rate and the initial brine salinity, with the production of metastable phases favoured at lower salinities and faster cooling rates. Different NaCl–H₂O assemblages exhibit characteristic near-infrared signatures that may provide a valuable tool for interpreting data collected by upcoming orbital missions to icy worlds. These results establish that the NaCl-H2O solid phase composition could be used as a new diagnostic probe of cryogenic processes on icy worlds, providing a means to reconstruct geological history of ocean-derived surface material and enabling space missions to assess the evolution of icy worlds across the outer Solar System.
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Sep 2026
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I15-Extreme Conditions
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Diamond Proposal Number(s):
[36011, 39563]
Abstract: This study identifies the structural origin of giant electrostrain in samarium-doped bismuth ferrite lead titanate (0.55Bi1-xSmxFeO3–0.45PbTiO3) ceramics. A giant peak-to-peak electrostrain (∼0.5 % at 60 kV cm–1) was obtained for compositions with x = 0.20 (20Sm) during initial poling, superior to Pb(Zr,Ti)O3 based ceramics with similar phase transition temperature of 275 °C, coupled with a piezoelectric coefficient of 276 pC/N comparable with hard PZT. While 20Sm is a macroscopically pseudo-cubic relaxor in its unpoled state, an irreversible, field-induced transformation gives a tetragonal (c/a∼1.115) ferroelectric phase as revealed by in-situ poling synchrotron X-ray diffraction and confirmed by transmission electron microscopy. The field-induced domain structure of the tetragonal structure could be reversibly switched under AC field after transformation. Quantitative strain analysis confirmed that the structural transformation accounts for approximately half of the total electrostrain, with the remainder by domain switching. These results highlight the importance of field-induced structural transformations for the development of high-performance piezoelectrics.
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Sep 2026
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I15-Extreme Conditions
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Diamond Proposal Number(s):
[7758, 8615]
Open Access
Abstract: The β′-Gd2(MoO4)3 phase is one of the most well-known multiferroic materials, exhibiting both ferroelectricity and ferroelasticity under ambient conditions, with a complex temperature-pressure phase diagram. In this study, we review the pressure-dependent behavior of the RE2(MoO4)3 compound family (where RE ≡ Pr–Ho), which crystallizes in the β′-phase, with the β-phase being the paraelectric parent structure. Eu, Tb, and Ho molybdates were synthesized via solid-state reactions, ensuring the absence of impurities. High-pressure experiments at DIAMOND synchrotron revealed that the β′-phase persists at low-pressures. At approximately 2 GPa, new peaks emerged, which were refined as a mixture of the β′-phase, other rare-earth molybdates, and oxides, some of which have been detected in earlier stages of synthesis. The β′-phase became distorted with increasing pressure while coexisting with these new phases, whose average unit cell volume was found to lie between that of the β′-phase and the formed distorted phase. Ultimately, this multiphase crystalline decomposition acts as a precursor to pressure-induced amorphization, leading to a loss of long-range periodicity without complete loss of local order. The onsets of pressure-induced decomposition, distortion of the β′-phase and apparent amorphization increase as the ionic radius of the rare-earth element decreases. This scenario of irreversible structural disorder accumulated through phase coexistence is consistent with previous studies and resolves a debate persisting for over half a century.
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Aug 2026
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I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[28402, 35088]
Open Access
Abstract: Keratin is an abundant structural fibrous protein and extremely recalcitrant biopolymer. β-Keratin is the major constituent of feathers, which, due to the widespread poultry industry, has become a major waste product. Biotechnological upcycling of feather waste has gained interest as various bacteria and fungi capable of degrading keratin have been isolated. These microorganisms produce proteases, termed keratinases, responsible for the enzymatic hydrolysis of keratin. The structural properties that confer keratinolytic activity to proteases are, however, not well understood. Here, we investigated the structure-function relationship of a subtilisin-like S8 endopeptidase (FerB) from the thermophile Fervidobacterium pennivorans strain T. FerB was crystallized and its structure solved to 1.5 Å resolution, revealing an auto-processed state where the pro-peptide domain is non-covalently attached to the catalytic domain. The carboxyl group of the scissile peptide bond is coordinated in the active site within hydrogen bonding distance of the catalytic triad’s serine residue. Unlike fervidolysin, no β-sandwich domains are present. However, a tyrosine-rich β-hairpin structure is found in the corresponding position within the FerB structure. Deletion of the β-hairpin reduced the protein’s integrity and keratinase activity.
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Aug 2026
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I15-Extreme Conditions
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Diamond Proposal Number(s):
[37838]
Open Access
Abstract: The structural behaviour of homoleptic xenon difluoride (XeF2) complexes [M(XeF2)6][SbF6]2 (M = Cu, Zn) under varying temperature and pressure has been investigated, aiming to resolve the disordered Jahn–Teller distortions in the copper complex (CuSb). At 200 K, both CuSb and its zinc analogue (ZnSb) crystallize in a layered CdCl2-type structure with the space group R3. Upon cooling below 170 (CuSb) and 160 K (ZnSb), both systems transition to isostructural phases in P1, with CuSb assuming an ordered Jahn–Teller distortion. The transformation is driven by the shortening and optimization of the Xe⋯F intermolecular contacts, forming stronger and more directional interactions, rather than by Jahn–Teller effects alone. This is supported by the observation of similar transitions in the Jahn–Teller-inactive Zn system. High-pressure experiments up to ∼2.8 GPa at room temperature show the structural stability of the high-symmetry phases, implicating kinetic barriers to further transformation. Additionally, the synthesis and structural characterization of a novel arsenic analogue, [Zn(XeF2)6][AsF6]2 (ZnAs), reveal similar layered motifs but distinct phase behaviour. Symmetry-mode analyses relate all observed phases through distortions of a common CdCl2 aristotype.
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Jul 2026
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[40212]
Open Access
Abstract: The `photometric selection' approach as a high throughput, sample tolerant, low cost and highly automatable method of carrying out serial crystallography is presented. Crystalline samples are loaded and distributed onto a simple transparent substrate and an in-line camera identifies crystals using image recognition algorithms from the computer vision project OpenCV. In contrast to established serial techniques, which generally require that crystal samples be refined with narrow size distributions and defined habits, the sample requirements when using photometric selection are shown to be minimal. We demonstrate how broadly effective photometric selection can be by collecting high-quality datasets from three exemplar systems: a small-molecule organometallic, a small-molecule organic and a metal–organic framework system. In contrast to previously established grid-scanning techniques, data collection using photometric selection can be up to six times faster.
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Jul 2026
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I03-Macromolecular Crystallography
Krios I-Titan Krios I at Diamond
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Diamond Proposal Number(s):
[19832]
Open Access
Abstract: We review the structural and functional characteristics of bacteriophages and bacteriocins (diffocins) that specifically target Clostridioides difficile, a significant healthcare concern due to its role in nosocomial infections. The advent of modern cryogenic electron microscopy (cryoEM) has revolutionized our understanding of these contractile injection systems, providing high-resolution insights into their mechanisms. We compare the structures of C. difficile phages and diffocins, highlighting their adaptations for penetrating the Gram-positive bacterial cell envelope – including the cell membrane, cell wall and proteinaceous surface layer. Diffocins, simpler in structure, utilize a combination of mechanical and enzymatic strategies, while some phages like ΦCD508 may rely on mechanical force alone. This review delves into the assembly and function of key components such as the contractile sheath, baseplate and receptor-binding proteins, offering a framework for engineering precision antimicrobials. We also present new experimental results, including refined cryoEM structures of the ΦCD508 pre- and post-contracted tail, a novel spontaneously contracted conformation and an X-ray crystal structure of a phage receptor-binding protein domain. This work underscores the potential of cryoEM in advancing our understanding of phage biology and its applications in developing targeted therapies against C. difficile.
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Jul 2026
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I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[38389]
Open Access
Abstract: A quaternary medium-entropy spinel oxide, (CrMnFeNi)3O4, was synthesized using a novel two-step metallurgical route comprising arc melting of an alloy precursor and oxidative annealing at 1000°C. Synchrotron X-ray diffraction and Rietveld refinement confirmed the formation of a single-phase spinel structure (
, a = 8.3694 Å). X-ray absorption near-edge structure (XANES) analysis revealed that Cr3+ and Ni2+ preferentially occupy octahedral sites, while Fe3+ occupies tetrahedral sites, with manganese distributed across both sublattices to maintain charge neutrality. When evaluated as an anode material for lithium-ion batteries, cyclic voltammetry revealed a multi-step lithiation mechanism, while electrochemical impedance spectroscopy tracked the kinetic evolution and indicated dynamic surface restructuring that enhances active material utilization and facilitates ion transport. The material exhibits stable long-term cycling over 1000 cycles at moderate and high current densities. Post-mortem analysis confirmed the loss of long-range crystalline order of the active material, validating the conversion mechanism.
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Jul 2026
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I03-Macromolecular Crystallography
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Elisa
Peirano
,
Laura
O'Regan
,
Philip
Harrer
,
Ivana
Dzinovic
,
Magda S.
Chegkazi
,
Petra
Havrankova
,
Theresa
Brunet
,
Rossella
Capolino
,
Claudia
Cesario
,
Stefania
Ferro
,
Eva
Hammar
,
Russia
Hà-Vinh Leuchter
,
Elisabetta
Indelicato
,
Maureen
Jacob
,
Lukas
Kunc
,
Henri
Margot
,
Oriano
Marin
,
Maria
Mazurkiewicz-Bełdzińska
,
Niccolò E.
Mencacci
,
Antonio
Novelli
,
Laura
Orec
,
Michael
Poschmann
,
Alexandra
Sitzberger
,
Ugo
Sorrentino
,
Melanie
Spanjaard
,
Matias
Wagner
,
Magdalena
Krygier
,
Sylvia
Boesch
,
Jan
Necpal
,
Matej
Skorvanek
,
Donald L.
Gilbert
,
Robert
Jech
,
Mark
Dodding
,
Roberto A.
Steiner
,
Michael
Zech
Open Access
Abstract: Background: Although de novo causation in dystonia is widely acknowledged, there have been only a few trio-sequencing analyses in this field. We sought to prioritise de novo variants in dystonia and characterise the clinical and molecular features associated with the top gene candidate identified after genomic matchmaking.
Methods: We (re)assessed exome-sequencing data for de novo variants in genes with strong mutational constraint in a sample of 257 dystonia trios. Via data sharing, we collected information on individuals with variants in KLC1, encoding a subunit of the axonal-transport motor protein kinesin-1. Biophysical, biochemical, and functional studies, including differential scanning fluorimetry, X-ray crystallography, fluorescence-polarisation measurements, and immunoprecipitation from cells were performed for representative KLC1 variants. Findings: Missense and loss-of-function de novo variants in constrained genes without implication in autosomal dominant or X-linked conditions were found in 11.7% (30/257) of cases with dystonia. We then ascertained 7 unrelated patients with movement and neurodevelopmental disorders who harboured distinct, predicted deleterious de novo KLC1 missense variants. These variants clustered within the cargo adaptor-binding tetratricopeptide repeat domain and 3 variants mapped to an identical amino-acid position. Highly similar infantile-onset dystonic-spastic phenotypes were observed in the subjects with the recurrently affected residue. For all functionally tested variants, we observed changes in KLC1 stability and/or altered binding behaviour to known kinesin-1 interactors, such as JIP3, previously associated with dystonia and neurodevelopmental impairment. Interpretation: Our research supports the existence of a kinesinopathy linked to KLC1, featuring phenotypic overlap with diseases related to mutational defects of key interactors of KLC1. The full dystonia de-novo variant compendium is reported as a resource for additional disease-gene discovery.
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Jul 2026
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