I11-High Resolution Powder Diffraction
I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[26668, 34452, 39378]
Open Access
Abstract: The absorption spectra of a series of Ce-oxo clusters (molecular nanoparticles) with sizes ranging from 3 to 100 Ce atoms per cluster are reported. The O 2p to Ce 4f charge-transfer absorption onset in these systems is unaffected by size and almost identical to that of 5 nm CeO(2−x) particles and other Ce based materials such as the metal–organic framework Ce-UiO-66. This clearly demonstrates that in CeO2 based systems, with highly localized 4f LUMO orbitals, quantum confinement effects are not influential on electronic structure. Importantly, this allows the use of ultrasmall ceria particles in (visible light) photochemical applications without detrimental band-gap enlarging size-effects. Changes in colour in CeO2 materials and these Ce-oxo clusters are instead clearly attributed to the presence of (defective) surface sites. Surface Ce(III) sites in mixed-valence clusters contribute a Ce(III)/Ce(IV) intervalence charge transfer transition in the visible region, which affects their colour. Ce24 clusters with a range of aliphatic and aromatic carboxylate ligands are studied, to compare the effect of surface ligands on the electronic structure. Ligand influence on the absorption spectra is only observed when highly conjugated (naphthyl) or strongly electron donating substituents (anisole or aniline) are present.
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May 2025
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I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[32711]
Open Access
Abstract: The tripartite motif (TRIM) family of RING-type E3 ligases catalyses the formation of many different types of ubiquitin chains, and as such, plays important roles in diverse cellular functions, ranging from immune regulation to cancer signalling pathways. Few ligands have been discovered for TRIM E3 ligases, and these E3s are under-represented in the rapidly expanding field of induced proximity. Here we present the identification of a novel covalent ligand for the PRYSPRY substrate binding domain of TRIM25. We employ covalent fragment screening coupled with high-throughput chemistry direct-to-biology optimisation to efficiently elaborate covalent fragment hits. We demonstrate that our optimised ligand enhances the in vitro auto-ubiquitination activity of TRIM25 and engages TRIM25 in live cells. We also present the X-ray crystal structure of TRIM25 PRYSPRY in complex with this covalent ligand. Finally, we incorporate our optimised ligand into heterobifunctional proximity-inducing compounds and demonstrate the in vitro targeted ubiquitination of a neosubstrate by TRIM25.
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May 2025
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Matthew J.
Beech
,
Edmond C.
Toma
,
Helen G.
Smith
,
Maria M.
Trush
,
Jit H. J.
Ang
,
Mei Y.
Wong
,
Chung H. J.
Wong
,
Hafiz S.
Ali
,
Zakia
Butt
,
Viha
Goel
,
Fernanda
Duarte
,
Alistair J. M.
Farley
,
Timothy R.
Walsh
,
Christopher J.
Schofield
Diamond Proposal Number(s):
[31353]
Open Access
Abstract: The Tet(X) flavin-dependent monooxygenases enable tetracycline antibiotic resistance by catalysing inactivating hydroxylation, so preventing inhibition of bacterial ribosomes. Tet(X) resistance is growing rapidly, threatening the efficacy of important last-resort tetracyclines such as tigecycline. Tet(X) inhibitors have potential to protect tetracyclines in combination therapies, but their discovery has been hampered by lack of high-throughput assays. We report the development of an efficient fluorescence polarisation Tet(X) binding assay employing a tetramethylrhodamine-glycyl-minocycline conjugate that enables inhibitor discovery. The assay was applied to tetracycline substrates and reported inhibitors, providing insight into their binding modes. Screening of a bioactive molecule library identified novel Tet(X) inhibitors, including psychoactive phenothiazine derivatives and the 5-HT4 agonist tegaserod, the activities of which were validated by turnover assays. Crystallographic studies of Tet(X4)-inhibitor complexes reveal two new inhibitor binding modes, importantly providing evidence for active site binding of Tet(X) inhibitors that do not share structural similarity with tetracycline substrates. In some cases, potentiation of tigecycline activity was observed in bacteria expressing Tet(X4). The combined results provide non-tetracycline scaffolds for development of potent Tet(X) inhibitors and highlight the need to evaluate the impact of non-antibiotics on antimicrobial resistance.
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May 2025
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[26879]
Open Access
Abstract: Treatment of 2-(pyrazol-1-yl)-6-fluoropyridine with one equiv of the appropriate 4-substituted 1H-pyrazole in the presence of sodium hydride gives moderate yields of 2-(pyrazol-1-yl)-6-(4-methylpyrazol-1-yl)pyridine (LMe), 2-(pyrazol-1-yl)-6-(4-fluoropyrazol-1-yl)pyridine (LF), 2-(pyrazol-1-yl)-6-(4-chloropyrazol-1-yl)pyridine (LCl) and 2-(pyrazol-1-yl)-6-(4-bromopyrazol-1-yl)pyridine (LBr). Single crystals of [Fe(LR)2]Z2 (R = Me, F or Br; Z− = BF4− or ClO4−) are often well-formed, but are poor diffractors of X-rays. An analysis of [Fe(LMe)2][ClO4]2 showed non-statistical positional disorder of the methyl substituents, leading to whole molecule disorder in each residue of the asymmetric unit. Single crystals of [Fe(LBr)2][BF4]2 are isomorphous with the LMe complex, and but less substituent disorder. All the complex salts are isomorphous by powder diffraction, and show thermal spin-transitions whose cooperativity differs from gradual (R = Me) to abrupt and hysteretic (R = Br). Some of the cooperative transitions exhibit irregular, closely spaced discontinuities which do not appear to be caused by crystallographic phase changes, and may reflect local heterogeneities caused by the cation disorder. No aspect of their crystal packing appears to correlate with their spin-transition cooperativity. However, weaker cooperativity may correlate with increased cation disorder in this system, which merits further investigation.
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Apr 2025
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I15-1-X-ray Pair Distribution Function (XPDF)
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Diamond Proposal Number(s):
[29957]
Open Access
Abstract: We report the solvent-free synthesis of a crystalline heterometallic imidazolate derivative with formula [Fe1Zn2(im)6(Him)2], designated MUV-25, incorporating both iron and zinc. The structure imposes strict positional constraints on the metal centres due to the lattice containing distinct geometric coordination sites, tetrahedral and octahedral. As a consequence, each metal is exclusively directed to its specific coordination site, ensuring precise spatial organization within the lattice. Atom locations were meticulously monitored utilizing X-ray diffraction (single crystal and total scattering) and XAS techniques, demonstrating that the tetrahedral sites are occupied exclusively by zinc, and the octahedral sites are occupied by iron. This combination of metal centres results, upon heating, in a structural phase transformation to the zni topology at a very low temperature. Further heating causes the melting of the solid, yielding a heterometallic MOF-derived glass. The methodology lays the groundwork for tailoring crystalline structures to advance the development of novel materials capable of melting and forming glasses upon cooling.
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Mar 2025
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I14-Hard X-ray Nanoprobe
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Diamond Proposal Number(s):
[28688]
Open Access
Abstract: Understanding the interactions between metal-based nanoparticles and biological systems in complex environments (e.g., the human body, soils, and marine settings) remains challenging, especially at the single-cell and nanoscale levels. Capturing the dynamics of these interactions, such as metal distribution, nanoparticle growth, or degradation, in their native state (in vivo) is particularly difficult. Here, we demonstrate the direct measurement of iron content in hydrated, magnetite-biomineralizing magnetotactic bacteria using synchrotron-based nanobeam–scanning X-ray fluorescence microscopy combined with a liquid cell environment. In addition to X-ray fluorescence imaging, we collected iron chemical speciation information from individual bacteria in liquid using X-ray absorption spectroscopy. To follow biomineralization in situ, we developed a microfluidic device to track magnetite nanoparticle formation over several hours under the X-ray beam. This approach highlights the potential of X-ray fluorescence microscopy in liquid cell setups to provide elemental and chemical insights into biological processes at the single-cell level. Combining X-ray nanobeam techniques with liquid cell devices will enable more “on-chip” experiments on metals in biological contexts to be conducted at the synchrotron.
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Mar 2025
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B22-Multimode InfraRed imaging And Microspectroscopy
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Leila
Abylgazina
,
Irena
Senkovska
,
Mariia
Maliuta
,
Christopher
Bachetzky
,
Marcus
Rauche
,
Kathrin
Pöschel
,
Johannes
Schmidt
,
Mark
Isaacs
,
David
Morgan
,
Michal
Otyepka
,
Eva
Otyepkova
,
Matthias
Mendt
,
Yogeshwar D.
More
,
Robin
Buschbeck
,
Andreas
Schneemann
,
Alla
Synytska
,
Andreas
Pöppl
,
Lukas M.
Eng
,
Jin-Chong
Tan
,
Eike
Brunner
,
Stefan
Kaskel
Diamond Proposal Number(s):
[30369]
Open Access
Abstract: A unique feature of flexible metal–organic frameworks (MOFs) is their ability to respond dynamically towards molecular stimuli by structural transitions, resulting in pore-opening and closing processes. One of the most intriguing modes is the “gating”, where the material transforms from the dense to the porous state. The conditions required for the solid phase structural transition are controlled by the kinetic barriers, including nucleation of the new phase commencing on the crystallite's outer surface. Thus, surface deformation may influence the nucleation, enabling deliberate tailoring of the responsivity. In the present contribution, we investigate how chemical surface treatments (surface deformation) affect the gate opening characteristics of a typical representative of gate pressure MOFs, DUT-8(Ni) ([Ni2(ndc)2(dabco)]n, ndc = 2,6-naphthalenedicarboxylate, dabco = 1,4-diazabicyclo[2.2.2]octane). A combination of various complementary advanced characterization techniques, such as NMR, nanoFTIR, terahertz, in situ XPS, in situ EPR spectroscopies, and inverse gas chromatography, are applied to unravel the changes in surface energy and mechanism of surface deformation.
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Mar 2025
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I03-Macromolecular Crystallography
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Diamond Proposal Number(s):
[32736]
Open Access
Abstract: Ribonucleosides are essential building blocks used extensively in antiviral and oligonucleotide therapeutics. A major challenge in the further development of nucleoside analogues for therapeutic applications is access to scalable and environmentally sustainable synthetic strategies. This study uses the type II nucleoside 2′-deoxyribosyltransferase from Lactobacillus leichmannii (LlNDT-2) to prepare a suite of ribonucleoside analogues using naturally-occurring uridine and cytidine sugar donors. Crystal structure and mutational analyses are used to define the substrate tolerance of the nucleobase exchange and the 2′-substituent of the nucleoside sugar donor. Nucleobase profiling identified acceptance of both purine and pyrimidine nucleobases. Finally, the scalability of the approach is showcased, enabling the preparation of ribonucleosides on millimolar scales. This biocatalytic strategy opens up opportunities to establish chemoenzymatic routes to prepare nucleoside analogues incorporating 2′ modifications that are of therapeutic importance.
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Dec 2024
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I11-High Resolution Powder Diffraction
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Matthew J.
Rosseinsky
,
Moinak
Dutta
,
Angelos B.
Canaj
,
Tilen
Knaflič
,
Christopher M.
Collins
,
Troy D.
Manning
,
Hongjun
Niu
,
Luke M.
Daniels
,
Aikaterini
Vriza
,
Luke A.
Johnson
,
Bhupendra
Mali
,
Yuri
Tanuma
,
Todd Wesley
Surta
,
John B.
Claridge
,
Neil
Berry
,
Denis
Arčon
,
Matthew S.
Dyer
Open Access
Abstract: We report the synthesis, structural characterization and magnetic properties of K3coronene, and demonstrate a computational screening workflow designed to accelerate the discovery of metal intercalated polycyclic aromatic hydrocarbon (PAH), a class of materials of interest following reports of superconductivity, but lacking demonstrated and understood characterised materials compositions. Coronene is identified as a suitable PAH candidate from a library of PAHs for potassium intercalation by computational screening of their electronic structure and of the void space in their crystal structures, targeting LUMO similarity to C60 and the availability of suitable sites to accommodate inserted cations. Convex hull calculations with energies from crystal structure prediction based on ion insertion into the identified void space of coronene suggest that the x = 3 composition in Kxcoronene is stable at 0 K, reinforcing the suitability of coronone for experimental investigation. Exploration of reaction conditions and compositions revealed that the mild reducing agent KH allows formation of K3coronene. The structure of K3coronene solved from synchrotron powder X-ray diffraction features extensive reorientation and associated disorder of coronene molecules compared with the parent pristine host. This is driven by K+ intercalation and occupation of sites both within and between the coronene stacks that are partially retained from the parent structure. This disruption of the host structure is greater when three cations are inserted per coronene than in reported metal PAH structures where the maximum ratio of cations to PAH is 2. Superconductivity is not observed, contrary to previous reports on Kxcoronene. The expected localised moment response of coronene3- is suppressed, which may be associated with the combination of extensive disorder and close coronene3- - coronene3- contacts.
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Dec 2024
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I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[23269]
Open Access
Abstract: De novo protein design is delivering new peptide and protein structures at a rapid pace. Many of these synthetic polypeptides form well-defined and hyperthermal-stable structures. Generally, however, less is known about the dynamic properties of the de novo designed structures. Here, we explore one aspect of dynamics in a series of de novo coiled-coil peptide assemblies: namely, peptide exchange within and between different oligomers from dimers through to heptamers. First, we develop a fluorescence-based reporter assay for peptide exchange that is straightforward to implement, and, thus, would be useful to others examining similar systems. We apply this assay to explore both homotypic exchange within single species, and heterotypic exchange between coiled coils of different oligomeric states. For the former, we provide detailed study for a dimeric coiled coil, CC-Di, finding a half-life for exchange of 4.2 ± 0.3 minutes at a peptide concentration of 200 µM. Interestingly, more broadly when assessing exchange across all of the oligomeric states, we find that some of the designs are faithful and only undergo homotypic strand exchange, whereas others are promiscuous and exchange to form unexpected hetero-oligomers. Finally, we develop two design strategies to improve the orthogonality of the different oligomers: (i) using alternate positioning of salt bridge interactions; and (ii) incorporating non-canonical repeats into the designed sequences. In so doing, we reconcile the promiscuity and deliver a set of faithful homo-oligomeric de novo coiled-coil peptides. Our findings have implications for the application of these and other coiled coils as modules in chemical and synthetic biology.
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Dec 2024
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