I03-Macromolecular Crystallography
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David
Hargreaves
,
Rodrigo J.
Carbajo
,
Michael S.
Bodnarchuk
,
Kevin
Embrey
,
Philip B.
Rawlins
,
Martin
Packer
,
Sébastien L.
Degorce
,
Alexander W.
Hird
,
Jeffrey W.
Johannes
,
Elisabetta
Chiarparin
,
Markus
Schade
Abstract: The structure-based design of small-molecule inhibitors targeting protein–protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.
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May 2023
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Diamond Proposal Number(s):
[18598]
Open Access
Abstract: Many secreted eukaryotic proteins are N-glycosylated with oligosaccharides composed of a high-mannose N-glycan core and, in the specific case of yeast cell-wall proteins, an extended α-1,6-mannan backbone carrying a number of α-1,2- and α-1,3-mannose substituents of varying lengths. α-Mannosidases from CAZy family GH92 release terminal mannose residues from these N-glycans, providing access for the α-endomannanases, which then degrade the α-mannan backbone. Most characterized GH92 α-mannosidases consist of a single catalytic domain, while a few have extra domains including putative carbohydrate-binding modules (CBMs). To date, neither the function nor the structure of a multi-domain GH92 α-mannosidase CBM has been characterized. Here, the biochemical investigation and crystal structure of the full-length five-domain GH92 α-1,2-mannosidase from Neobacillus novalis (NnGH92) with mannoimidazole bound in the active site and an additional mannoimidazole bound to the N-terminal CBM32 are reported. The structure of the catalytic domain is very similar to that reported for the GH92 α-mannosidase Bt3990 from Bacteroides thetaiotaomicron, with the substrate-binding site being highly conserved. The function of the CBM32s and other NnGH92 domains was investigated by their sequential deletion and suggested that whilst their binding to the catalytic domain was crucial for the overall structural integrity of the enzyme, they appear to have little impact on the binding affinity to the yeast α-mannan substrate. These new findings provide a better understanding of how to select and optimize other multi-domain bacterial GH92 α-mannosidases for the degradation of yeast α-mannan or mannose-rich glycans.
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May 2023
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Open Access
Abstract: Herein, the alcoholysis of furfuryl alcohol in a series of SBA-15-pr-SO3H catalysts with different pore sizes is reported. Elemental analysis and NMR relaxation/diffusion methods show that changes in pore size have a significant effect on catalyst activity and durability. In particular, the decrease in catalyst activity after catalyst reuse is mainly due to carbonaceous deposition, whereas leaching of sulfonic acid groups is not significant. This effect is more pronounced in the largest-pore-size catalyst C3, which rapidly deactivates after one reaction cycle, whereas catalysts with a relatively medium and small average pore size (named, respectively, C2 and C1) deactivate after two reaction cycles and to a lesser extent. CHNS elemental analysis showed that C1 and C3 experience a similar amount of carbonaceous deposition, suggesting that the increased reusability of the small-pore-size catalyst can be attributed to the presence of SO3H groups mostly present on the external surface, as corroborated by results on pore clogging obtained by NMR relaxation measurements. The increased reusability of the C2 catalyst is attributed to a lower amount of humin being formed and, at the same time, reduced pore clogging, which helps to maintain accessible the internal pore space.
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May 2023
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I03-Macromolecular Crystallography
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Mauricio P.
Contreras
,
Hsuan
Pai
,
Muniyandi
Selvaraj
,
Amirali
Toghani
,
David M.
Lawson
,
Yasin
Tumtas
,
Cian
Duggan
,
Enoch Lok Him
Yuen
,
Clare E. M.
Stevenson
,
Adeline
Harant
,
Abbas
Maqbool
,
Chih-Hang
Wu
,
Tolga O.
Bozkurt
,
Sophien
Kamoun
,
Lida
Derevnina
Diamond Proposal Number(s):
[18565]
Open Access
Abstract: Parasites counteract host immunity by suppressing helper nucleotide binding and leucine-rich repeat (NLR) proteins that function as central nodes in immune receptor networks. Understanding the mechanisms of immunosuppression can lead to strategies for bioengineering disease resistance. Here, we show that a cyst nematode virulence effector binds and inhibits oligomerization of the helper NLR protein NRC2 by physically preventing intramolecular rearrangements required for activation. An amino acid polymorphism at the binding interface between NRC2 and the inhibitor is sufficient for this helper NLR to evade immune suppression, thereby restoring the activity of multiple disease resistance genes. This points to a potential strategy for resurrecting disease resistance in crop genomes.
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May 2023
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[21053]
Abstract: N-9-Fluorenylmethyloxycarbonyl (Fmoc)- and C-tertiary butyl (t-Bu)-protected glutamate (L-2), bearing a phenanthroline moiety at the side residue, forms 1D supramolecular assemblies via H-bonding as well as undergoing π-stacking interactions to afford crystals or gels that depend on the shape-complementarity of coexisting alcohols, as demonstrated by structural analyses on these assemblies by means of single-crystal X-ray diffractometry and supplemented with small- and wide-angle X-ray scattering data. Moreover, the rheological measurements on the gels help to define a model for when gels and crystals are expected and found. These observations and conclusions highlight an important, but not very appreciated, aspect of solute–solvent interactions within supramolecular assemblies that can allow the constituent-aggregating molecules in some systems to exhibit high selectivity toward the structures of their solvents. The consequences of this selectivity, as demonstrated here by single-crystal and powder X-ray diffraction data, can lead to self-assembled structures which alter completely the bulk phase properties and morphology of the materials. In that regard, rheological measurements have helped to develop a model to explain when gels and phase-separated mixtures of crystals and solvents are expected.
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May 2023
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B21-High Throughput SAXS
I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[31323, 31668]
Open Access
Abstract: The allosteric regulation of biomolecules, such as enzymes, enables them to adapt and alter their conformation to fit specific substrates, expressing different functionalities in response to stimuli. Different stimuli can also trigger synthetic coordination cages to change their shape, size, and nuclearity by reconfiguring the dynamic metal–ligand bonds that hold them together. Here we demonstrate an abiological system consisting of different organic subcomponents and ZnII metal ions, which can respond to simple stimuli in complex ways. A ZnII20L12 dodecahedron transforms to give a larger ZnII30L12 icosidodecahedron through subcomponent exchange, as an aldehyde that forms bidentate ligands is displaced in favor of one that forms tridentate ligands together with a penta-amine subcomponent. In the presence of a chiral template guest, the same system that produced the icosidodecahedron instead gives a ZnII15L6 truncated rhombohedral architecture through enantioselective self-assembly. Under specific crystallization conditions, a guest induces a further reconfiguration of either the ZnII30L12 or ZnII15L6 cages to yield an unprecedented ZnII20L8 pseudo-truncated octahedral structure. The transformation network of these cages shows how large synthetic hosts can undergo structural adaptation through the application of chemical stimuli, opening pathways to broader applications.
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May 2023
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I05-ARPES
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A. Garrison
Linn
,
Peipei
Hao
,
Kyle N.
Gordon
,
Dushyant
Narayan
,
Bryan S.
Berggren
,
Nathaniel
Speiser
,
Sonka
Reimers
,
Richard P.
Campion
,
Vít
Novák
,
Sarnjeet S.
Dhesi
,
Timur K.
Kim
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Cephise
Cacho
,
Libor
Šmejkal
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Tomáš
Jungwirth
,
Jonathan D.
Denlinger
,
Peter
Wadley
,
Daniel S.
Dessau
Diamond Proposal Number(s):
[24224]
Open Access
Abstract: Tetragonal CuMnAs is a room temperature antiferromagnet with an electrically reorientable Néel vector and a Dirac semimetal candidate. Direct measurements of the electronic structure of single-crystalline thin films of tetragonal CuMnAs using angle-resolved photoemission spectroscopy (ARPES) are reported, including Fermi surfaces (FS) and energy-wavevector dispersions. After correcting for a chemical potential shift of ≈− 390 meV (hole doping), there is excellent agreement of FS, orbital character of bands, and Fermi velocities between the experiment and density functional theory calculations. In addition, 2×1 surface reconstructions are found in the low energy electron diffraction (LEED) and ARPES. This work underscores the need to control the chemical potential in tetragonal CuMnAs to enable the exploration and exploitation of the Dirac fermions with tunable masses, which are predicted to be above the chemical potential in the present samples.
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May 2023
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I19-Small Molecule Single Crystal Diffraction
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Mei-Yan
Gao
,
Andrey A.
Bezrukov
,
Bai-Qiao
Song
,
Meng
He
,
Sousa Javan
Nikkhah
,
Shi-Qiang
Wang
,
Naveen
Kumar
,
Shaza
Darwish
,
Debobroto
Sensharma
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Chenghua
Deng
,
Jiangnan
Li
,
Lunjie
Liu
,
Rajamani
Krishna
,
Matthias
Vandichel
,
Sihai
Yang
,
Michael J.
Zaworotko
Open Access
Abstract: Ultramicroporous materials can be highly effective at trace gas separations when they offer a high density of selective binding sites. Herein, we report that sql-NbOFFIVE-bpe-Cu, a new variant of a previously reported ultramicroporous square lattice, sql, topology material, sql-SIFSIX-bpe-Zn, can exist in two polymorphs. These polymorphs, sql-NbOFFIVE-bpe-Cu-AA (AA) and sql-NbOFFIVE-bpe-Cu-AB (AB), exhibit AAAA and ABAB packing of the sql layers, respectively. Whereas NbOFFIVE-bpe-Cu-AA (AA) is isostructural with sql-SIFSIX-bpe-Zn, each exhibiting intrinsic 1D channels, sql-NbOFFIVE-bpe-Cu-AB (AB) has two types of channels, the intrinsic channels and extrinsic channels between the sql networks. Gas and temperature induced transformations of the two polymorphs of sql-NbOFFIVE-bpe-Cu were investigated by pure gas sorption, single-crystal X-ray diffraction (SCXRD), variable temperature powder X-ray diffraction (VT-PXRD), and synchrotron PXRD. We observed that the extrinsic pore structure of AB resulted in properties with potential for selective C3H4/C3H6 separation. Subsequent dynamic gas breakthrough measurements revealed exceptional experimental C3H4/C3H6 selectivity (270) and a new benchmark for productivity (118 mmol g–1) of polymer grade C3H6 (purity >99.99%) from a 1:99 C3H4/C3H6 mixture. Structural analysis, gas sorption studies, and gas adsorption kinetics enabled us to determine that a binding “sweet spot” for C3H4 in the extrinsic pores is behind the benchmark separation performance. Density-functional theory (DFT) calculations and Canonical Monte Carlo (CMC) simulations provided further insight into the binding sites of C3H4 and C3H6 molecules within these two hybrid ultramicroporous materials, HUMs. These results highlight, to our knowledge for the first time, how pore engineering through the study of packing polymorphism in layered materials can dramatically change the separation performance of a physisorbent.
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May 2023
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I10-Beamline for Advanced Dichroism
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Diamond Proposal Number(s):
[23338]
Abstract: In this thesis, the static and dynamic properties of magnetic multilayer samples were studied using a variety of experimental techniques, based both at Exeter and the Diamond Light Source (DLS) and Advanced Light Source (ALS) synchrotron facilities. The exchange interaction, which acts to align spins, is a fundamental part in these magnetic multilayer samples. First, the glancing angle deposition (GLAD) technique was investigated as a tool for creating magnetic multilayers with exciting new exchange interactions. For this, Co thin films were grown by DC magnetron sputtering to tailor the magnetic anisotropy of the samples. These Co samples were structurally characterized using x-ray diffraction (XRD) and transmission electron microscopy (TEM). Vibrating sample magnetometry (VSM) was then performed to investigate the magnetic properties of the thin films as a result of the GLAD technique. From this, the necessary conditions for effective anisotropy control using the GLAD technique were identified. Synchrotron x-ray measurements, such as x-ray magnetic circular / linear dichroism (XMCD/XMLD) for static measurements, are vital for investigating magnetic multilayer samples with elemental resolution. To add depth-sensitivity to the synchrotron measurements, the idea of an ultra-thin Mn “spy layer” was investigated by inserting different thicknesses (tMn) of Mn into the NiFe layer in a FePt / NiFe bilayer. The effect on the static magnetic properties was studied using VSM and XMCD hysteresis loops before structural information was obtained using scanning transmission electron microscopy (STEM). The magnetization dynamics were probed using vector network analyzer ferromagnetic resonance (VNA-FMR) and element resolved x-ray ferromagnetic resonance (XFMR) measurements. From this, the ideal “spy layer” thickness of Mn was found to lie in the region 0Å < tMn < 5Å . Spin currents are a dynamic process found in magnetic multilayers and are driven by the exchange interaction. The measurement of a transverse charge current generated via the inverse spin Hall effect (ISHE) has become the principal technique for observing spin currents. During ISHE measurements, parasitic microwave effects were observed and a method to separate out the inverse spin Hall effect was identified. This method was then tested for a reference YIG / Pt bilayer. A more complex NiFe / NiO / Pd / FeCo sample was then studied using this procedure and the ISHE voltage was identified, despite the presence of additional parasitic effects. In addition to the DC spin current component, there is an AC spin current contribution. The AC spin current component was also investigated for the NiFe / NiO / Pd / FeCo sample series using XMCD, XMLD and XFMR measurements. The XMCD and XMLD data revealed the Ni and (Fe)Co spins possess perpendicular in-plane coupling relative to the magnetic moments within the NiO layer. To understand the magnetization dynamics in these samples, an evanescent spin wave model was invoked. This provides crucial insights for interpreting spin current propagation through NiO. Through the combination of work described above, new avenues for the fabrication of magnetic multilayers and the measurement of the magnetization dynamics in such systems are presented to yield a more complete understanding of the crucial role of the exchange interaction in the magnetization dynamics of magnetic multilayers.
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May 2023
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[20876]
Open Access
Abstract: Cyclic porphyrin oligomers have been studied as models for photosynthetic light-harvesting antenna complexes and as potential receptors for supramolecular chemistry. Here, we report the synthesis of unprecedented β,β-directly linked cyclic zinc porphyrin oligomers, the trimer (CP3) and tetramer (CP4), by Yamamoto coupling of a 2,3-dibromoporphyrin precursor. Their three-dimensional structures were confirmed by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analyses. The minimum-energy geometries of CP3 and CP4 have propeller and saddle shapes, respectively, as calculated using density functional theory. Their different geometries result in distinct photophysical and electrochemical properties. The smaller dihedral angles between the porphyrin units in CP3, compared with CP4, result in stronger π-conjugation, splitting the ultraviolet–vis absorption bands and shifting them to longer wavelengths. Analysis of the crystallographic bond lengths indicates that the central benzene ring of the CP3 is partially aromatic [harmonic oscillator model of aromaticity (HOMA) 0.52], whereas the central cyclooctatetraene ring of the CP4 is non-aromatic (HOMA –0.02). The saddle-shaped structure of CP4 makes it a ditopic receptor for fullerenes, with affinity constants of (1.1 ± 0.4) × 105 M–1 for C70 and (2.2 ± 0.1) × 104 M–1 for C60, respectively, in toluene solution at 298 K. The formation of a 1:2 complex with C60 is confirmed by NMR titration and single-crystal X-ray diffraction.
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May 2023
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