I24-Microfocus Macromolecular Crystallography
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Rachel
Bolton
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Moritz M.
Machelett
,
Jack
Stubbs
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Danny
Axford
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Nicolas
Caramello
,
Lucrezia
Catapano
,
Martin
Maly
,
Matthew J.
Rodrigues
,
Charlotte
Cordery
,
Graham J.
Tizzard
,
Fraser
Macmillan
,
Sylvain
Engilberge
,
David
Von Stetten
,
Takehiko
Tosha
,
Hiroshi
Sugimoto
,
Jonathan A. R.
Worrall
,
Jeremy S.
Webb
,
Mike
Zubkov
,
Simon
Coles
,
Eric
Mathieu
,
Roberto A.
Steiner
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Garib
Murshudov
,
Tobias E.
Schrader
,
Allen M.
Orville
,
Antoine
Royant
,
Gwyndaf
Evans
,
Michael A.
Hough
,
Robin L.
Owen
,
Ivo
Tews
Diamond Proposal Number(s):
[15722, 14493, 23570]
Open Access
Abstract: The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes generally encode two different types of FutA iron-binding proteins: periplasmic FutA2 ABC transporter subunits bind Fe(III), while cytosolic FutA1 binds Fe(II). Owing to their small size and their economized genome Prochlorococcus ecotypes typically possess a single futA gene. How the encoded FutA protein might bind different Fe oxidation states was previously unknown. Here, we use structural biology techniques at room temperature to probe the dynamic behavior of FutA. Neutron diffraction confirmed four negatively charged tyrosinates, that together with a neutral water molecule coordinate iron in trigonal bipyramidal geometry. Positioning of the positively charged Arg103 side chain in the second coordination shell yields an overall charge-neutral Fe(III) binding state in structures determined by neutron diffraction and serial femtosecond crystallography. Conventional rotation X-ray crystallography using a home source revealed X-ray-induced photoreduction of the iron center with observation of the Fe(II) binding state; here, an additional positioning of the Arg203 side chain in the second coordination shell maintained an overall charge neutral Fe(II) binding site. Dose series using serial synchrotron crystallography and an XFEL X-ray pump–probe approach capture the transition between Fe(III) and Fe(II) states, revealing how Arg203 operates as a switch to accommodate the different iron oxidation states. This switching ability of the Prochlorococcus FutA protein may reflect ecological adaptation by genome streamlining and loss of specialized FutA proteins.
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Mar 2024
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I03-Macromolecular Crystallography
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Arathy
Jose
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Daniel
Guest
,
Remi
Legay
,
Graham J.
Tizzard
,
Simon
Coles
,
Mariliza
Derveni
,
Edward
Wright
,
Lester
Marrison
,
Alpha A.
Lee
,
Aaron
Morris
,
Matt
Robinson
,
Frank
Von Delft
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Daren
Fearon
,
Lizbe
Koekemoer
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Tetiana
Matviuk
,
Anthony
Aimon
,
Christopher J.
Schofield
,
Tika R.
Malla
,
Nir
London
,
Barnaby W.
Greenland
,
Mark C.
Bagley
,
John
Spencer
Diamond Proposal Number(s):
[19301]
Open Access
Abstract: The pentafluorosulfanyl (-SF5) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5-containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.
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Feb 2022
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I19-Small Molecule Single Crystal Diffraction
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Alexander J.
Bukvic
,
Arron L.
Burnage
,
Graham J.
Tizzard
,
Antonio J.
Martinez-Martinez
,
Alasdair I.
Mckay
,
Nicholas H.
Rees
,
Bengt E.
Tegner
,
Tobias
Krämer
,
Heather
Fish
,
Mark R.
Warren
,
Simon J.
Coles
,
Stuart A.
Macgregor
,
Andrew S.
Weller
Diamond Proposal Number(s):
[20300, 17308]
Open Access
Abstract: Using solid-state molecular organometallic (SMOM) techniques, in particular solid/gas single-crystal to single-crystal reactivity, a series of σ-alkane complexes of the general formula [Rh(Cy2PCH2CH2PCy2)(ηn:ηm-alkane)][BArF4] have been prepared (alkane = propane, 2-methylbutane, hexane, 3-methylpentane; ArF = 3,5-(CF3)2C6H3). These new complexes have been characterized using single crystal X-ray diffraction, solid-state NMR spectroscopy and DFT computational techniques and present a variety of Rh(I)···H–C binding motifs at the metal coordination site: 1,2-η2:η2 (2-methylbutane), 1,3-η2:η2 (propane), 2,4-η2:η2 (hexane), and 1,4-η1:η2 (3-methylpentane). For the linear alkanes propane and hexane, some additional Rh(I)···H–C interactions with the geminal C–H bonds are also evident. The stability of these complexes with respect to alkane loss in the solid state varies with the identity of the alkane: from propane that decomposes rapidly at 295 K to 2-methylbutane that is stable and instead undergoes an acceptorless dehydrogenation to form a bound alkene complex. In each case the alkane sits in a binding pocket defined by the {Rh(Cy2PCH2CH2PCy2)}+ fragment and the surrounding array of [BArF4]− anions. For the propane complex, a small alkane binding energy, driven in part by a lack of stabilizing short contacts with the surrounding anions, correlates with the fleeting stability of this species. 2-Methylbutane forms more short contacts within the binding pocket, and as a result the complex is considerably more stable. However, the complex of the larger 3-methylpentane ligand shows lower stability. Empirically, there therefore appears to be an optimal fit between the size and shape of the alkane and overall stability. Such observations are related to guest/host interactions in solution supramolecular chemistry and the holistic role of 1°, 2°, and 3° environments in metalloenzymes.
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Mar 2021
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[2871]
Abstract: A series of “light metal” metal–organic frameworks containing secondary building units (SBUs) based on Li+ and Na+ cations have been prepared using the silicon-centered linkers MexSi(p-C6H4CO2H)4-x (x = 2, 1, 0). The unipositive charge, small size, and oxophilic nature of the metal cations give rise to some unusual and unique SBUs, including a three-dimensional nodal structure built from sodium and oxygen ions when using the triacid linker (x = 1). The same linker with Li+ cations generated a chiral, helical SBU, formed from achiral starting materials. One-dimensional rod SBUs are observed for the diacid (x = 2) and tetra-acid (x = 0) linkers with both Li+ and Na+ cations, where the larger size of Na+ compared to Li+ leads to subtle differences in the constitution of the metal nodes.
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Nov 2018
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[17308]
Abstract: Solid/gas Single–Crystal to Single–Crystal (SC–SC) hydrogenation of appropriate diene precursors forms the corresponding σ–alkane complexes [Rh(Cy2P(CH2)nPCy2)(L)][BArF4] (n = 3, 4) and [RhH(Cy2P(CH2)2(CH)(CH2)2PCy2)(L)][BArF4] (n = 5, L = norbornane, NBA; cyclooctane, COA). Their struc-tures, as determined by single–crystal X-ray diffraction, have cations exhibiting Rh···H–C σ–interactions which are modulated by both the chelating ligand and the identity of the alkane, while all sit in an octahedral anion–microenvironment. These range from chelating η2,η2 Rh···H–C (e.g. [Rh(Cy2P(CH2)nPCy2)(η2η2–NBA)][BArF4], n = 3 and 4), through to more weakly bound η1 Rh··H–C in which C–H activation of the chelate backbone has also occurred (e.g. [RhH(Cy2P(CH2)2(CH)(CH2)2PCy2)(η1–COA)][BArF4]) and ultimately to systems where the alkane is not ligated with the metal center, but sits encapsulated in the supporting anion microenvironment – [Rh(Cy2P(CH2)3PCy2)][COA⊂BArF4] – in which the metal center instead forms two intramolecular agostic η1 Rh···H–C interactions with the phosphine cyclohexyl groups. CH2Cl2 adducts formed by displacement of the η1–alkanes in solution (n = 5; L = NBA, COA), [RhH(Cy2P(CH2)2(CH)(CH2)2PCy2)(η1–ClCH2Cl)][BArF4], are characterized crystallographically. Analyses via periodic DFT, QTAIM, NBO and NCI calculations, alongside variable temperature solid–state NMR spectroscopy, provide snapshots marking the onset of Rh σ-alkane interactions along a C···H activation trajectory. These are negligible in [Rh(Cy2P(CH2)3PCy2)][COA⊂BArF4]; in [RhH(Cy2P(CH2)2(CH)(CH2)2PCy2)(η1–COA)][BArF4] σC–H→Rh σ-donation is supported by Rh→σ*C-H ‘pregostic’ donation; and in [Rh(Cy2P(CH2)nPCy2)(η2η2-NBA)][BArF4] (n = 2-4) σ-donation dominates, supported by classical Rh(dπ)→σ*C-H π-back donation. Dispersive interactions with the [BArF4]- anions and Cy substituents further stabilize the alkanes within the binding pocket.
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Oct 2018
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[6916]
Abstract: The syntheses, characterization and experimental solid state X-ray structures of five low-spin paramagnetic 2-pyridyl-(1,2,3)-triazole-copper compounds, [Cu(Ln)2Cl2], are presented in this study, for the following five Ln ligands: L2 = 2-(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)pyridine), L6 = 2-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)pyridine), L7 = 4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)benzonitril), L8 = 2-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine) and L9 = 2-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)pyridine). These five [Cu(Ln)2Cl2] complexes each contain two bidentate 2-pyridyl-(1,2,3)-triazole (Ln) and two chloride ions as ligands, with the Cu-N(pyridine) bonds, Cu-N(triazole) and Cu-Cl bonds trans to each other. All five [Cu(Ln)2Cl2] compounds display elongation Jahn-Teller distortion, either along opposite Cu-N(triazole) bonds, or along opposite Cu-Cl bonds, as indicated by their obtained solid state crystal structures. Quantum chemistry calculations, using density functional theory, indicated however that elongation Jahn-Teller distortion is in fact possible along any two opposite bonds in these octahedral compounds with the elongation distortion along the opposite Cu-N(triazole) bonds being the most stable structure.
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Sep 2018
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[8521]
Abstract: We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-L-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from L-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of 1H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein–protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by 1H-15N HSQC NMR titration experiments.
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Mar 2015
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[8521]
Abstract: New tetrabenzotriazaporphyrins are reported that are functionalised at the meso-position. The derivatives functionalised with meso-bromophenyl substituents are synthesised using an improved variation on the traditional reaction between phthalonitriles and Grignard reagents. For all other new derivatives, a modern protocol is employed that gives convenient access to these challenging materials by template co-macrocyclisation between phthalonitriles and aryl-aminoisoindoline derivatives like 15. The newly developed procedure allows design and synthesis of elaborate, functional composites and this is demonstrated by synthesis of meso-pyrenylTBTAP 24, a linked double chromophore in which the two complementary units lie perpendicular to each other and therefore have minimal ground state interaction.
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Oct 2014
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I19-Small Molecule Single Crystal Diffraction
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Open Access
Abstract: Although crystals suffering radiation damage is a well-known and studied phenomena for macromolecular crystallography[1], as far as we are aware there appears to be no such published work relating to chemical crystallography. However, there are numerous anecdotal accounts of disintegrating crystals and resolution progressively dropping off that have been ascribed to radiation damage. Since the start of operations on the small molecule synchrotron beamline I19[2] at Diamond Light Source, there have been multiple comments from several users observing sample damage in the beam. The UK National Crystallography Service[3] handles a wide variety of samples and a number of these have experienced radiation damage. In order to understand the causes and symptoms of this effect in greater detail some controlled experiments were performed. A series of experiments were conducted on crystals that were known to undergo radiation damage in order to determine some quantification of the effect. Additionally the aim is to understand what one might be able to do to mitigate against the damage caused and determine whether the effects observed are similar to those of macromolecular crystallography. The effects of varying the collection temperature, overall dose, dose rate and wavelength of X-ray used were all tested and normalised for each sample. Samples where radiation damage has been observed were chosen and were also required to be air stable and preferably not suffer from solvent loss, in order to minimize problems of nonreproducibility. Those chosen to probe this effect were: 1. A gold complex Ö has potential to suffer heavily from absorption effects. 2. A nickel complex with significant solvent water Ö this could to some extent mimic the behaviour exhibited by proteins. 3. A small organic compound Ö an example of unexpected decay. The poster will summarise the results of these experiments and contrast them with data collected on a high intensity rotating anode laboratory source
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Aug 2014
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[6916, 8521]
Abstract: The crystal structures of a new polymorph and seven new derivatives of 2-(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine have been characterized and examined along with three structures from the literature to identify trends in their intermolecular contact patterns and packing arrangements in order to develop an insight into the crystallization behaviour of this class of compound. Seven unique C-H···X contacts were identified in the structures and three of these are present in four or more structures, indicating that these are reliable supramolecular synthons. Analysis of the packing arrangements of the molecules using XPac identified two closely related supramolecular constructs that are present in eight of the 11 structures; in all cases, the structures feature at least one of the three most common intermolecular contacts, suggesting a clear relationship between the intermolecular contacts and the packing arrangements of the structures. Both the intermolecular contacts and packing arrangements appear to be remarkably consistent between structures featuring different functional groups, with the expected exception of the carboxylic acid derivative 4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl) benzoic acid (L11), where the introduction of a strong hydrogen-bonding group results in a markedly different supramolecular structure being adopted. The occurrence of these structural features has been compared with the packing efficiency of the structures and their melting points in order to assess the relative favourability of the supramolecular structural features in stabilizing the crystal structures.
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Apr 2014
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