I03-Macromolecular Crystallography
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Rob F.
Lammers
,
Qin
Su
,
Laura
Mazo
,
Wendy A.
Offen
,
Roelof
Ottenhoff
,
Mats J.
Bulterman
,
Martijn
Van Der Lienden
,
Maria J.
Ferraz
,
Florian
Küllmer
,
Zahid
Ilhan
,
Hans
Van Den Elst
,
Ingeborg
Van Der Made
,
Cindy P. A. A.
Van Roomen
,
Anne
De Jongh
,
Adrianus M. C. H.
Van Den Nieuwendijk
,
Rolf G.
Boot
,
Noam
Zelcer
,
Gideon J.
Davies
,
Carme
Rovira
,
Herman S.
Overkleeft
,
Johannes M. F. G.
Aerts
,
Marta
Artola
Diamond Proposal Number(s):
[39189]
Open Access
Abstract: Neutral glucosylceramidase GBA2 is a retaining β-d-glucosidase involved in sphingolipid metabolism and implicated in neurological lysosomal storage disorders, yet the lack of highly selective chemical inhibitors has hindered efforts to disentangle its function from that of glucosylceramide synthase (GCS) and lysosomal glucosylceramidase (GBA1). Here, we report the development of the first brain-penetrant, covalent inhibitor that selectively inactivates GBA2 in vivo. Building on β-d-arabinofuranose-configured (β-d-Araf) cyclitol aziridine activity-based probes previously shown to covalently and selectively label GBA2, we designed and synthesized a focused library of electrophile-bearing cyclitols, including epoxides, cyclic sulfates, and a diverse set of N-alkyl aziridines. Biochemical evaluation of their inhibitory activity against GBA1, GBA2, GBA3 and GCS revealed that several N-alkyl aziridines are highly selective, nanomolar GBA2 inhibitors. Lead compounds also demonstrated metabolic stability in murine plasma, robust cellular activity and high selectivity in living cells, with no detectable GCS inhibition. Notably, octyl-alkyne aziridine 5 selectively inhibited GBA2 in mouse brain, representing the first covalent GBA2 inhibitor with demonstrated in vivo activity and brain permeability. Together, these results establish β-d-Araf cyclitol aziridine 5 as a versatile inhibitor for selective, covalent GBA2 inhibition, well suited to dissect GBA2 biology in vivo, particularly in neurological lysosomal storage disorders.
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Sep 2026
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B23-Circular Dichroism
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Diamond Proposal Number(s):
[41438]
Open Access
Abstract: Understanding the interplay between different forms of chirality in organic materials is critical for tuning and optimizing their (chir)optical properties. There is a growing interest in chiral chromophores such as bay-substituted perylene diimides (PDIs) due to their intrinsic helicity (M/P) which, at a higher level of organization, can also generate supramolecular chirality (Ms/Ps). The relationship between helical and supramolecular chirality governs interchromophore coupling, rotatory strengths, and subsequently circular dichroism (CD) and circularly polarized luminescence (CPL) spectra. Herein, we report the first PDI dimers that match helical and supramolecular chirality, e.g., PP–Ps. In agreement with theory, this chiral synergy contributes to enhanced CD and broadband CPL with high CPL brightness, properties of significant value for optical filtering in next-generation chiral sensors and displays.
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Sep 2026
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I03-Macromolecular Crystallography
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Luise
Pallasdies
,
Helen
Barber
,
Mihwa
Lee
,
Laura
Burchill
,
Ho N. N.
Ho
,
Adam W. E.
Stewart
,
Artur
Nastasovici
,
Hanna
Sanne-Wander
,
Dilushini T.
Rathnayake
,
Vinzenz
Hofferek
,
Leila
Jebeli
,
Taylor A.
Mcdaniels
,
Malcolm J.
Mcconville
,
Robert A.
Field
,
Sacha
Pidot
,
Nichollas E.
Scott
,
Yi
Jin
,
Spencer J.
Williams
Diamond Proposal Number(s):
[31850]
Abstract: Small aminoorganosulfonates are reservoirs of carbon, nitrogen, and sulfur in marine and host-associated ecosystems. Homotaurine, a C3-aminoorganosulfonate produced by marine algae and present in algal-derived foods, is comparatively well documented, but its complete microbial catabolism has remained unresolved. Here we identify a complete bacterial pathway for homotaurine catabolism in Caballeronia jiangsuensis strain McCoy, isolated by metabolic enrichment from soil by growth on homotaurine. Growth, proteomic, metabolomic, biochemical, structural, and heterologous-expression analyses show that homotaurine is imported and oxidatively deaminated to sulfopropanoate, then converted to sulfolactate through E-sulfoacrylate by SpuABCD and SpuIJ, enzymes related to succinate dehydrogenase and fumarase. Sulfolactate is cleaved by redundant SuyAB sulfolyases to release pyruvate and sulfite, which is oxidized and excreted as sulfate, completing biomineralization. Crystal structures of the HtaA homotaurine-binding protein and SuyAB2 sulfolyase reveal ligand recognition and provide a structural framework for sulfolactate cleavage. Hidden Markov model searches and Tara Oceans and human gut metagenomes show that the core sulfopropanoate-to-sulfolactate module is widespread in marine Proteobacteria, especially Roseobacter-lineage bacteria, and occurs more narrowly in human gut-associated sulfur-metabolizing taxa such as Bilophila wadsworthia. This pathway connects algal, dietary, and xenobiotic C3-aminoorganosulfonates to microbial carbon, nitrogen, and sulfur cycling, and identifies sulfopropanoate turnover as a conserved module in organosulfonate metabolism.
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Sep 2026
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I15-Extreme Conditions
I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[41632, 36628, 38508]
Open Access
Abstract: Hybrid lead halide perovskites exhibit a delicate interplay between average crystallographic symmetry, local structural disorder and A-site orientational dynamics, giving rise to unusual vibrational and electronic behavior. Here, we combine large-scale molecular dynamics with a density-functional-theory-accurate machine learning force field to resolve the structural dynamics of perovskites across mesoscopic length scales. In formamidinium lead iodide (FAPbI3), we identify a high-temperature α phase with dynamic local order and correlated tilt nanodomains, an ordered γ phase with long-range a+a+a+ tilt coherence, and, below ∼100 K, a history-dependent γ′ state consisting of locally γ-like nanoscale regions separated by sharp twin-like boundaries. This low-temperature disordered state is not a distinct bulk polymorph, but a kinetically arrested metastable twin-domain network selected by the interplay between shallow tilt energetics and slowing FA reorientation. This picture is supported by our low-temperature X-ray diffuse scattering measurements and accounts for the broadened low-energy vibrational response found in the simulations. Furthermore, this unique structural landscape imprints a spatially varying electronic disorder with implications for macroscopic optoelectronic properties, reflected in substantial band-edge broadening retained at low temperature. Our results reconcile the debated low-temperature behavior of FAPbI3 in terms of competition between ordered and arrested structural states, and more broadly identify molecular reorientation as a kinetic selector of metastable framework topology in soft molecular crystals, placing thermal history on equal footing with composition as a determinant of structural and optoelectronic properties.
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Aug 2026
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I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[34438, 31440, 37593]
Open Access
Abstract: In targeted protein degradation (TPD), specific subcellular proteins are removed by routing them to the ubiquitin-proteasome, autophagy, or lysosome machinery. For instance, proteolysis-targeting chimeras (PROTACs) are synthetic heterobifunctional small molecules that simultaneously bind the target and an E3 ubiquitin ligase to drive ubiquitination and degradation by the proteasome. Despite considerable success, designing such molecules is challenging, and the number of currently addressable ubiquitin E3 ligases is limited. Here, we design a heterobifunctional de novo protein to trigger the degradation of a common cancer target, resulting in a desired phenotypic output. First, we developed a highly stable and adaptable helix–turn–helix scaffold for presenting multiple binding sites. Next, we use computational protein design to incorporate and embellish hot-spot-binding sites to target the antiapoptotic mediators BCL-xL and MCL-1. We show a 75% success rate for creating submicromolar binders against these targets. Crystal structures of the complexes confirmed the designed binding poses. Then, we designed short linear motifs (SLiMs) into the loop of the scaffold to recruit KLHL20 and the ubiquitin ligase machinery. These designs have low micromolar affinity for KLHL20 comparable to that of the natural SLiMs. Moreover, the bifunctionalized proteins degrade BCL-xL in cells, leading to apoptosis.
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Aug 2026
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[31353]
Open Access
Abstract: We report X-ray crystallographic structures of the Azotobacter vinelandii nitrogenase MoFe protein showing the 8Fe-7S electron-transfer P-cluster in four redox states. Using electrochemical poising of protein crystals, together with in crystallo EPR spectroscopic verification of the redox state, we obtain structures showing the P-cluster at PN, P1+, P2+, and P3+ levels. This provides a detailed structural characterization of P-cluster rearrangement between the catalytically relevant PN and P1+ levels and the first experimental confirmation that the S = 7/2 P3+ state is structurally similar to P2+. These studies pave the way for future understanding of the structure–function relationship in nitrogenase catalysis.
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Aug 2026
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B07-B1-Versatile Soft X-ray beamline: High Throughput ES1
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Lewis G.
Parker
,
Frances K.
Towers Tompkins
,
Jake M.
Seymour
,
Ekaterina
Gousseva
,
Christopher D.
Smith
,
Roger A.
Bennett
,
Pilar
Ferrer
,
David C.
Grinter
,
Claudia
Kolbeck
,
Dennis
Hein
,
Garlef
Wartner
,
Robert
Seidel
,
Denis
Céolin
,
Robert
Temperton
,
Robert G.
Palgrave
,
Richard P.
Matthews
,
Kevin R. J.
Lovelock
Diamond Proposal Number(s):
[33378, 35207, 36765, 36196]
Open Access
Abstract: Anion interactions with cations/molecules are crucial across chemistry and biology: in battery electrolytes, synthesis, atmospheric processes, and protein denaturation. Selecting the optimum anion represents an immense challenge, as anion interactions are diverse and complex. Descriptors are needed that quantitatively capture the ability of anions to interact with cations and molecules. However, only a small number of experimental anion interaction descriptors exist, all with similar limitations. Here we show that core-level anion electron binding energies, EB(core,anion), can be used to produce a new atomic-level descriptor for each of the key donor elements for anion interactions (O, N, F, Cl, Br, I, S), the element-specific donor number (DNE-XPS). DNE-XPS descriptors are intrinsic, capturing the anion interaction abilities independent of any probe, countercation, or solvent. DNE-XPS descriptors are also interpretable, as EB(core,anion) and therefore DNE-XPS are proportional to the electrostatic potential at the specific donor atom nucleus. Experimental core-level X-ray photoelectron spectroscopy (XPS) is used to measure EB(core,anion) and therefore DNE-XPS. Furthermore, DNE-XPS descriptors are produced easily and at low cost using lone-anion-SMD (solvation model density) calculations, a significant advance on the current anion descriptors, greatly reducing and potentially removing the need for experimental anion characterization. This work will greatly facilitate anion selection, especially for complex anions capable of forming interactions through multiple different atoms. We envisage our calculation method enabling the production of a very large database of DNE-XPS for each key element, ideal for use as machine learning training data sets.
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Aug 2026
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I11-High Resolution Powder Diffraction
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Diamond Proposal Number(s):
[32893, 39378]
Open Access
Abstract: Systematic strategies to design properties such as ferroelectricity or magnetoelectric coupling are well-established in simple perovskite materials, but they remain scarce in more complex framework structures. Using a hexagonal polytype of the ternary Manganite AMnO3 (A= Ba, Sr, Ca) as a model system, we introduce a symmetry-guided design principle in which an inversion-breaking rigid-unit mode (RUM) serves as a single structural instability generating both polar and ferromagnetic orders within a bulk antiferromagnetic material. Symmetry analysis and first-principles calculations reveal that cooperative tilts of the Mn2O9 bioctahedral dimers generate a spontaneous polarization, and in the antiferromagnetically ordered state, they also induce a ferromagnetic moment. High-resolution diffraction and magnetic susceptibility measurements show that the structural and magnetic orders persist as high as 450 and 280 K, respectively, highlighting the untapped potential of framework structures that deviate from simple perovskite motifs to be designed to host useful ferroic properties. Our approach establishes a transferable symmetry-based framework for engineering ferroelectric and magnetoelectric states across chemically diverse framework architectures.
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Aug 2026
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I02-Macromolecular Crystallography
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Elena
De Vita
,
Adam M.
Thomas
,
Delia
Brustur
,
Montse
Tersa
,
Rita
Petracca
,
Shradda R.
Vadodaria
,
Deborah A.
Briggs
,
Jack W.
Houghton
,
Thomas
Lanyon-Hogg
,
Gregory B.
Craven
,
R. Marc L.
Morgan
,
Alan
Armstrong
,
David J.
Mann
,
Katharine
Lodge
,
Alistair N.
Hume
,
Ernesto
Cota
,
Edward W.
Tate
Diamond Proposal Number(s):
[17221]
Open Access
Abstract: RAB27A and RAB27B are homologous small GTPases that regulate intracellular vesicle trafficking, orchestrating endocytic and exocytic processes that affect cellular communication, immune responses, and the dynamics of the cellular microenvironment. Through their interactions with effector proteins, RAB27A/B plays roles in tumor metastasis and chronic inflammation. However, pharmacological modulation of their activity faces challenges typical of small GTPases, including a lack of well-defined pockets outside the conserved GTP binding site and large RAB27-effector protein–protein interaction (PPI) surfaces. Here, we present the discovery and development of the first cell-active, rationally designed covalent inhibitors of the RAB27-effector interaction, targeting a non-conserved cysteine residue flanking the PPI interface. An electrophile-first biochemical screen led to a novel class of acrylamide covalent inhibitors, and X-ray crystallography structure-guided design led to optimized inhibitors and probes that enantioselectively target RAB27A/B Cys123 in cells. Potency and selectivity were confirmed through biochemical and cellular assays, including chemical proteomics and phenotype recapitulation in melanocytes, alongside a matched inactive enantioprobe control. In contrast, a previously reported compound, Nexinhib-20, was found to be cytotoxic and to exert its activity through non-selective reactivity. This work provides the first toolbox of cell-active chemical probes for RAB27 that can be used in future studies to shed light on the function of this protein and its potential as a therapeutic target.
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Aug 2026
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I22-Small angle scattering & Diffraction
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Diamond Proposal Number(s):
[35754]
Open Access
Abstract: Proteins with intrinsically disordered regions (IDRs) perform essential cellular functions despite lacking stable structures, challenging the traditional structure–function paradigm. Neurofilament-light (NFL) proteins self-assemble into bottlebrush filaments, whose disordered tail domains mediate nematic hydrogel formation critical for neuronal integrity. Mutations in NFL are linked to Charcot–Marie–Tooth (CMT) disease, yet their molecular effects remain unclear. Here, aiming to gain insight into these molecular mechanisms, we combine small-angle X-ray scattering, microscopy, and deep-learning conformational analysis to investigate CMT-associated NFL tail mutations. We find that these mutations compact the hydrogel, disrupt filament nematic order by generating microdomains, and alter water retention dynamics by shifting sequence-dependent conformational ensembles, leading to macroscopic network rearrangements. These findings demonstrate how subtle sequence changes in IDRs modulate protein network organization and function, offering structural insights into IDR-related pathologies.
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Jul 2026
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