I16-Materials and Magnetism
I22-Small angle scattering & Diffraction
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Abstract: Wedge‐shaped molecules, such as dendrons, are among the most important building blocks for directed supramolecular self‐assembly. Here we present a new approach aimed at widening the range and complexity of potential mesophases by introducing double‐tapered mesogens. Two series of compounds are presented, both alkali metal salts (Li, Na, Cs) of 3,4,5‐tris‐alkoxybenzoic acid with a second tapered tris‐alkoxyaryl group attached at the end of an alkoxy chain. The double‐tapered compounds all display an unusual hexagonal columnar phase consisting of one ionic and three non‐ionic columns per unit cell. The cation size has an unexpectedly drastic effect on unit cell size. Unlike most columnars, the current phases show unusually high dimensional stability on heating, and high stiffness in spite of being 80‐85% aliphatic, attributed to their molecular topology. The described approach may lead to co‐assemblies of multifunctional materials, e.g. parallel p‐ and n‐semiconducting nanowires or parallel ionic and electronic conductors.
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Jul 2019
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Diamond Proposal Number(s):
[12346]
Abstract: Bacterial production of β‐lactamases with carbapenemase activity is a global health threat. The active sites of class D carbapenemases such as OXA‐48, which is of major clinical importance, uniquely contain a carbamylated lysine residue which is essential for catalysis. Although there is significant interest in characterizing this post‐translational modification, and it is a promising inhibition target, protein carbamylation is challenging to monitor in solution. We report the use of 19F‐NMR spectroscopy to monitor the carbamylation state of 19F‐labelled OXA‐48. This method was used to investigate the interactions of OXA‐48 with clinically used serine β‐ lactamase inhibitors, including avibactam and vaborbactam. Crystallographic studies on 19F‐labelled OXA‐48 provide a structural rationale for the sensitivity of the 19F‐label to active site interactions. The overall results demonstrate the use of 19F‐NMR to monitor reversible covalent post‐translational modifications.
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Jul 2019
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I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[13467]
Abstract: The chemical basis for protecting organisms against the toxic effect imposed by excess cuprous ions is to constrain this through high‐affinity binding sites that employ cuprous‐thiolate coordination chemistries. In bacteria, a family of cysteine rich four helix‐bundle proteins utilise thiolate chemistry to bind up to 80 cuprous ions. These proteins have been termed copper storage proteins (Csp). The present study investigates cuprous ion loading to the Csp from Streptomyces lividans (SlCsp) using a combination of X‐ray crystallography, site‐directed mutagenesis and stopped‐flow reaction kinetics with either aquatic cuprous ions or a chelating donor. We illustrate that at low cuprous ion concentrations, copper is loaded exclusively into an outer core region of SlCsp via one end of the four helix‐bundle, facilitated by a set of three histidine residues. X‐ray crystallography reveals the existence of polynuclear cuprous‐thiolate clusters culminating in the assembly of a tetranuclear [Cu4(μ2‐S‐Cys)4(Νδ1‐His)] cluster in the outer core. As more cuprous ions are loaded, the cysteine lined inner core of SlCsp fills with cuprous ions but in a fluxional and dynamic manner with no evidence for the assembly of further intermediate polynuclear cuprous‐thiolate clusters as observed in the outer core. Using site‐directed mutagenesis a key role for His107 in the efficient loading of cuprous ions from a donor is established. A model of copper loading to SlCsp is proposed and discussed.
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May 2019
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Diamond Proposal Number(s):
[14331]
Abstract: Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape‐diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3‐rich molecular scaffolds. The resulting set of 80 fragments was highly three‐dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high‐throughput protein crystallography against Aurora‐A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape‐diverse screening collections to be more fully assessed.
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Apr 2019
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Diamond Proposal Number(s):
[9948]
Abstract: Cell signaling by small G proteins uses an ON to OFF signal based on conformational changes following the hydrolysis of GTP to GDP and release of dihydrogen phosphate (Pi). The catalytic mechanism of GTP hydrolysis by RhoA is strongly accelerated by a GAP protein and is now well defined, but timing of inorganic phosphate release and signal change remains unresolved. We have generated a quaternary complex for RhoA‐GAP‐GDP‐Pi. Its 1.75 Å crystal structure shows geometry for ionic and hydrogen bond coordination of GDP and Pi in an intermediate state. It enables the selection of a QM core for DFT exploration of a 20 H‐bonded network. This identifies serial locations of the two mobile protons from the original nucleophilic water molecule, showing how they move in three rational steps to form a stable quaternary complex. It also suggests how two additional proton transfer steps can facilitate Pi release.
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Apr 2019
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[13639]
Abstract: This study details attempts to access N‐heterocyclic carbenes (NHCs) featuring the diazaborolyl group, {(HCNDipp)2B}, as one or both of the N‐bound substituents. Attempts to isolate N‐heterocyclic carbenes based around imidazolylidene or related heterocycles, are characterized by facile N‐to‐C migration of the boryl substituent. In the cases of imidazolium precursors bearing one N‐bound diazaboryl group and one methyl substituent, deprotonation leads to the generation of the target carbenes, which can be characterized in situ by NMR measurements, and trapped by reactions with metal fragments and elemental selenium. The half‐lives of the free carbenes at room temperature range from 4‐50 h (depending on the pattern of ancillary substituents) with N‐to‐C2 migration of the boryl function being shown to be the predominant rearrangement pathway. Kinetic studies show this to be a first order process that occurs with an entropy of activation close to zero. DFT calculations imply that an intramolecular 1,2‐shift is mechanistically feasible, with calculated activation energies of the order of 90‐100 kJ mol‐1 reflecting the retention of significant aromatic character in the imidazole ring in the transition state. Trapping of the carbene allows for evaluation of steric and electronic properties via systems of the type LAuCl, LRh(CO)2Cl and LSe. A highly unsymmetrical (but nonetheless bulky) steric profile and moderately enhanced σ‐donor capabilities (compared to IMes) are revealed.
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Dec 2018
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[15059]
Abstract: Two new heteroleptic metal‐organic framework materials show strong adsorption of H2 and ethanol. [Co2(L1)(bdc)2], where L1=N1,N4‐bis(4‐pyridinylmethyl)‐2,5‐dimethylbenzene‐1,4‐diamine and bdc is benzene‐1,4‐dicarboxylate, has a twofold interpenetrating pillared layer structure with pcu topology. It has a stepped, hysteretic EtOH adsorption that can be related to complicated phase and structural transformation behaviour that occurs on de‐solvation and re‐solvation, including major conformational changes to the geometry of the flexible L1 ligand. [Co2(L1)(bpdc)2], where bpdc=biphenyl‐4,4′‐dicarboxylate, has a unique six‐connected self‐catenating framework structure. Solvation changes occur without significant structural change and a partially‐hydrolysed material binds its own decomposition products as guests.
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Dec 2018
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Marta
Artola
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Chi-lin
Kuo
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Stephen
Mcmahon
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Verena
Oehler
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Thomas
Hansen
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Martijn
Van Der Lienden
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Xu
He
,
Hans
Van Den Elst
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Bogdan I.
Florea
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Allison R.
Kermode
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Gijsbert A.
Van Der Marel
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Tracey M.
Gloster
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Jeroen D. C.
Codée
,
Herman S.
Overkleeft
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Johannes M. F. G.
Aerts
Diamond Proposal Number(s):
[14980]
Open Access
Abstract: Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity‐based glycosidase probes (ABPs). Direct 3‐amino‐2‐(trifluoromethyl)quinazolin‐4(3H)‐one‐mediated aziridination of l‐ido‐configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α‐l‐iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity‐based manner with human recombinant α‐l‐iduronidase (rIDUA, Aldurazyme®). The structures of IDUA when complexed with the inhibitors in a non‐covalent transition state mimicking form and a covalent enzyme‐bound form provide insights into its conformational itinerary. Inhibitors 1–3 adopt a half‐chair conformation in solution (4H3 and 3H4), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1–3 may need to overcome an energy barrier in order to switch from the 4H3 conformation to the transition state (2, 5B) binding conformation before reacting and adopting a covalent 5S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.
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Nov 2018
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[8464]
Abstract: Post‐assembly reaction of a dynamic covalent iminoboronate system following addition of Cp2Co resulted in the formation of a series of new reductively coupled dianionic dimers via C‐C bond formation. The boronate dimers formed as a mixture of BN‐containing isomeric products: diastereomers rac5 and meso5, with coupled five‐membered rings, and enantiomeric rac6, with a fused six‐membered ring bicyclic system from C‐C bond formation and rearrangement of the B‐N bonds. Each isomer was identified using 1H NMR spectroscopy in combination with single crystal X‐ray structure determination. Interestingly, interconversion between the coupled five‐membered rings (rac5) and fused bicyclic systems (rac6) was found to occur through an unprecedented breaking and reforming of the B‐N covalent bond. Further, the coupled products could be converted quantitatively back to their iminoboronate precursors with addition of the electron abstractor Ph3C+.
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Jul 2018
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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
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Abstract: The new complexes [Ru(TAP)2(11‐CN‐dppz]2+ [Ru(TAP)2(11‐Br‐dppz]2+and [Ru(TAP)2(11,12‐CN2‐dppz)]2+ are reported. The addition of nitrile substituents to the dppz ligand of the DNA photooxidising complex [Ru(TAP)2(dppz)]2+ promotes π‐stacking interactions and ordered binding to DNA, as shown by X‐ray crystallography. The structure of lambda‐[Ru(TAP)2(11‐CN‐dppz)]2+ with the DNA duplex d(TCGGCGCCGA)2 shows, for the first time with this class of complex, a closed intercalation cavity with an AT base pair at the terminus. The structure obtained is compared to that formed with the 11,12‐dinitrile and 11‐Br derivatives, highlighting the stabilisation of syn guanine by this enantiomer when the terminal basepair is GC. In contrast the AT basepair has the normal Watson‐Crick orientation, highlighting the difference in charge distribution between the two purine bases and the complementarity of the dppz‐purine interaction. The asymmetry of the cavity highlights the importance of the purine‐dppz‐purine stacking interaction.
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Jul 2018
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