I03-Macromolecular Crystallography
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Takashi
Miura
,
Tika R.
Malla
,
C. David
Owen
,
Anthony
Tumber
,
Lennart
Brewitz
,
Michael A.
Mcdonough
,
Eidarus
Salah
,
Naohiro
Terasaka
,
Takayuki
Katoh
,
Petra
Lukacik
,
Claire
Strain-Damerell
,
Halina
Mikolajek
,
Martin A.
Walsh
,
Akane
Kawamura
,
Christopher J.
Schofield
,
Hiroaki
Suga
Diamond Proposal Number(s):
[27088]
Open Access
Abstract: γ-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of γ-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic γ2,4-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (Mpro). Two kinds of cyclic γ2,4-amino acids, cis-3-aminocyclobutane carboxylic acid (γ1) and (1R,3S)-3-aminocyclopentane carboxylic acid (γ2), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent Mpro inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ1 at the fourth position, manifests a 5.2 nM dissociation constant. An Mpro:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ1 interacts with the S1′ catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and Mpro enabled production of a variant with a 5-fold increase in potency.
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May 2023
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I19-Small Molecule Single Crystal Diffraction
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Zhipeng
Zhou
,
Lei
Zhang
,
Yonghang
Yang
,
Inigo J.
Vitórica-Yrezábal
,
Honglei
Wang
,
Fanglin
Tan
,
Li
Gong
,
Yuyao
Li
,
Pohua
Chen
,
Xin
Dong
,
Zihao
Liang
,
Jing
Yang
,
Chao
Wang
,
Yuexian
Hong
,
Yi
Qiu
,
Armin
Gölzhäuser
,
Xudong
Chen
,
Haoyuan
Qi
,
Sihai
Yang
,
Wei
Liu
,
Junliang
Sun
,
Zhikun
Zheng
Diamond Proposal Number(s):
[31627]
Abstract: A core feature of covalent organic frameworks (COFs) is crystallinity, but current crystallization processes rely substantially on trial and error, chemical intuition and large-scale screening, which typically require harsh conditions and low levels of supersaturation, hampering the controlled synthesis of single-crystal COFs, particularly on large scales. Here we report a strategy to produce single-crystal imine-linked COFs in aqueous solutions under ambient conditions using amphiphilic amino-acid derivatives with long hydrophobic chains. We propose that these amphiphilic molecules self-assemble into micelles that serve as dynamic barriers to separate monomers in aqueous solution (nodes) and hydrophobic compartments of the micelles (linkers), thereby regulating the polymerization and crystallization processes. Disordered polyimines were obtained in the micelle, which were then converted into crystals in a step-by-step fashion. Five different three-dimensional COFs and a two-dimensional COF were obtained as single crystals on the gram scale, with yields of 92% and above.
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Apr 2023
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I22-Small angle scattering & Diffraction
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Abstract: Quasicrystals are intriguing structures that have long-range positional correlations but no periodicity in real space, and typically with rotational symmetries that are ‘forbidden’ in conventional periodic crystals. Here, we present a two-dimensional columnar liquid quasicrystal with dodecagonal symmetry. Unlike previous dodecagonal quasicrystals based on random tiling, a honeycomb structure based on a strictly quasiperiodic tessellation of tiles is observed. The structure consists of dodecagonal clusters made up of triangular, square and trapezoidal cells that are optimal for local packing. To maximize the presence of such dodecagonal clusters, the system abandons periodicity but adopts a quasiperiodic structure that follows strict packing rules. The stability of random-tiling dodecagonal quasicrystals is often attributed to the entropy of disordering when strict tiling rules are broken, at the sacrifice of the long-range positional order. However, our results demonstrate that quasicrystal stability may rest on energy minimization alone, or with only minimal entropic intervention.
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Mar 2023
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[21497]
Abstract: The regioselective functionalization of C60 remains challenging, while the enantioselective functionalization of C60 is difficult to explore due to the need for complex chiral tethers or arduous chromatography. Metal–organic cages have served as masks to effect the regioselective functionalization of C60. However, it is difficult to control the stereochemistry of the resulting fullerene adducts through this method. Here we report a means of defining up to six stereocentres on C60, achieving enantioselective fullerene functionalization. This method involves the use of a metal–organic cage built from a chiral formylpyridine. Fullerenes hosted within the cavity of the cage can be converted into a series of C60 adducts through chemo-, regio- and stereo-selective Diels–Alder reactions with the edges of the cage. The chiral formylpyridine ultimately dictates the stereochemistry of these chiral fullerene adducts without being incorporated into them. Such chiral fullerene adducts may become useful in devices requiring circularly polarized light manipulation.
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Dec 2022
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B23-Circular Dichroism
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Jessica
Wade
,
Francesco
Salerno
,
Rachel C.
Kilbride
,
Dong Kuk
Kim
,
Julia A.
Schmidt
,
Joel A.
Smith
,
Luc M.
Leblanc
,
Emma H.
Wolpert
,
Adebayo A.
Adeleke
,
Erin R.
Johnston
,
Jenny
Nelson
,
Tadashi
Mori
,
Kim E.
Jelfs
,
Sandrine
Heutz
,
Matthew J.
Fuchter
Diamond Proposal Number(s):
[29151]
Abstract: Chiral π-conjugated molecules bring new functionality to technological applications and represent an exciting, rapidly expanding area of research. Their functional properties, such as the absorption and emission of circularly polarized light or the transport of spin-polarized electrons, are highly anisotropic. As a result, the orientation of chiral molecules critically determines the functionality and efficiency of chiral devices. Here we present a strategy to control the orientation of a small chiral molecule (2,2′-dicyano[6]helicene) by the use of organic and inorganic templating layers. Such templating layers can either force 2,2′-dicyano[6]helicene to adopt a face-on orientation and self-assemble into upright supramolecular columns oriented with their helical axis perpendicular to the substrate, or an edge-on orientation with parallel-lying supramolecular columns. Through such control, we show that low- and high-energy chiroptical responses can be independently ‘turned on’ or ‘turned off’. The templating methodologies described here provide a simple way to engineer orientational control and, by association, anisotropic functional properties of chiral molecular systems for a range of emerging technologies.
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Oct 2022
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[17773]
Abstract: The combination of computational design and directed evolution could offer a general strategy to create enzymes with new functions. So far, this approach has delivered enzymes for a handful of model reactions. Here we show that new catalytic mechanisms can be engineered into proteins to accelerate more challenging chemical transformations. Evolutionary optimization of a primitive design afforded an efficient and enantioselective enzyme (BH32.14) for the Morita–Baylis–Hillman (MBH) reaction. BH32.14 is suitable for preparative-scale transformations, accepts a broad range of aldehyde and enone coupling partners and is able to promote selective monofunctionalizations of dialdehydes. Crystallographic, biochemical and computational studies reveal that BH32.14 operates via a sophisticated catalytic mechanism comprising a His23 nucleophile paired with a judiciously positioned Arg124. This catalytic arginine shuttles between conformational states to stabilize multiple oxyanion intermediates and serves as a genetically encoded surrogate of privileged bidentate hydrogen-bonding catalysts (for example, thioureas). This study demonstrates that elaborate catalytic devices can be built from scratch to promote demanding multi-step processes not observed in nature.
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Dec 2021
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I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
I04-Macromolecular Crystallography
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Jurgen
Brem
,
Tharindi
Panduwawala
,
Jon Ulf
Hansen
,
Joanne
Hewitt
,
Edgars
Liepins
,
Pawel
Donets
,
Laura
Espina
,
Alistair J. M.
Farley
,
Kirill
Shubin
,
Gonzalo Gomez
Campillos
,
Paula
Kiuru
,
Shifali
Shishodia
,
Daniel
Krahn
,
Robert K.
Leśniak
,
Juliane
Schmidt
,
Karina
Calvopina
,
María-Carmen
Turrientes
,
Madeline E.
Kavanagh
,
Dmitrijs
Lubriks
,
Philip
Hinchliffe
,
Gareth W.
Langley
,
Ali F.
Aboklaish
,
Anders
Eneroth
,
Maria
Backlund
,
Andrei G.
Baran
,
Elisabet I.
Nielsen
,
Michael
Speake
,
Janis
Kuka
,
John
Robinson
,
Solveiga
Grinberga
,
Lindsay
Robinson
,
Michael A.
Mcdonough
,
Anna M.
Rydzik
,
Thomas M.
Leissing
,
Juan Carlos
Jimenez-Castellanos
,
Matthew B.
Avison
,
Solange
Da Silva Pinto
,
Andrew D.
Pannifer
,
Marina
Martjuga
,
Emma
Widlake
,
Martins
Priede
,
Iva
Hopkins Navratilova
,
Marek
Gniadkowski
,
Anna Karin
Belfrage
,
Peter
Brandt
,
Jari
Yli-Kauhaluoma
,
Eric
Bacque
,
Malcolm G. P.
Page
,
Fredrik
Björkling
,
Jonathan M.
Tyrrell
,
James
Spencer
,
Pauline A.
Lang
,
Pawel
Baranczewski
,
Rafael
Cantón
,
Stuart P.
Mcelroy
,
Philip S.
Jones
,
Fernando
Baquero
,
Edgars
Suna
,
Angus
Morrison
,
Timothy R.
Walsh
,
Christopher J.
Schofield
Open Access
Abstract: Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure–activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL–carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
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Dec 2021
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Alistair J.
Scott
,
Ai
Niitsu
,
Huong T.
Kratochvil
,
Eric J. M.
Lang
,
Jason T.
Sengel
,
William M.
Dawson
,
Kozhinjampara R.
Mahendran
,
Marco
Mravic
,
Andrew
Thomson
,
R. Leo
Brady
,
Lijun
Liu
,
Adrian J.
Mulholland
,
Hagan
Bayley
,
William F.
Degrado
,
Mark I.
Wallace
,
Derek N.
Woolfson
Abstract: The design of peptides that assemble in membranes to form functional ion channels is challenging. Specifically, hydrophobic interactions must be designed between the peptides and at the peptide–lipid interfaces simultaneously. Here, we take a multi-step approach towards this problem. First, we use rational de novo design to generate water-soluble α-helical barrels with polar interiors, and confirm their structures using high-resolution X-ray crystallography. These α-helical barrels have water-filled lumens like those of transmembrane channels. Next, we modify the sequences to facilitate their insertion into lipid bilayers. Single-channel electrical recordings and fluorescent imaging of the peptides in membranes show monodisperse, cation-selective channels of unitary conductance. Surprisingly, however, an X-ray structure solved from the lipidic cubic phase for one peptide reveals an alternative state with tightly packed helices and a constricted channel. To reconcile these observations, we perform computational analyses to compare the properties of possible different states of the peptide.
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May 2021
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I15-1-X-ray Pair Distribution Function (XPDF)
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Bikash Kumar
Shaw
,
Ashlea R.
Hughes
,
Maxime
Ducamp
,
Stephen
Moss
,
Anup
Debnath
,
Adam F.
Sapnik
,
Michael F.
Thorne
,
Lauren N.
Mchugh
,
Andrea
Pugliese
,
Dean S.
Keeble
,
Philip
Chater
,
Juan M.
Bermudez-Garcia
,
Xavier
Moya
,
Shyamal K.
Saha
,
David A.
Keen
,
François-Xavier
Coudert
,
Frédéric
Blanc
,
Thomas
Bennett
Diamond Proposal Number(s):
[20038]
Abstract: Several organic–inorganic hybrid materials from the metal–organic framework (MOF) family have been shown to form stable liquids at high temperatures. Quenching then results in the formation of melt-quenched MOF glasses that retain the three-dimensional coordination bonding of the crystalline phase. These hybrid glasses have intriguing properties and could find practical applications, yet the melt-quench phenomenon has so far remained limited to a few MOF structures. Here we turn to hybrid organic–inorganic perovskites—which occupy a prominent position within materials chemistry owing to their functional properties such as ion transport, photoconductivity, ferroelectricity and multiferroicity—and show that a series of dicyanamide-based hybrid organic–inorganic perovskites undergo melting. Our combined experimental–computational approach demonstrates that, on quenching, they form glasses that largely retain their solid-state inorganic–organic connectivity. The resulting materials show very low thermal conductivities (~0.2 W m−1 K−1), moderate electrical conductivities (10−3–10−5 S m−1) and polymer-like thermomechanical properties.
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May 2021
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B18-Core EXAFS
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Diamond Proposal Number(s):
[14239]
Abstract: Platinum functions exceptionally well as a nanoparticulate catalyst in many important fields, such as in the removal of atmospheric pollutants, but it is scarce, expensive and not always sufficiently durable. Here, we report a perovskite system in which 0.5 wt% Pt is integrated into the support and its subsequent conversion through exsolution to achieve a resilient catalyst. Owing to the instability of most Pt oxides at high temperatures, a thermally stable platinum oxide precursor, barium platinate, was used to preserve the platinum as an oxide during the solid-state synthesis in an approach akin to the Trojan horse legend. By tailoring the procedure, it is possible to produce a uniform equilibrated structure with active emergent Pt nanoparticles strongly embedded in the perovskite surface that display better CO oxidation activity and stability than those of conventionally prepared Pt catalysts. This catalyst was further evaluated for a variety of reactions under realistic test environments—CO and NO oxidation, diesel oxidation catalysis and ammonia slip reactions were investigated.
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May 2021
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