I03-Macromolecular Crystallography
|
Diamond Proposal Number(s):
[11235]
Open Access
Abstract: The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53’s oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1MET(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.
|
Sep 2016
|
|
I04-Macromolecular Crystallography
|
Dongsheng
Zhu
,
Huocong
Huang
,
Daniel
Pinkas
,
Jinfeng
Luo
,
Debolina
Ganguly
,
Alice E.
Fox
,
Emily
Arner
,
Qiuping
Xiang
,
Zheng-Chao
Tu
,
Alex N.
Bullock
,
Rolf A
Brekken
,
Ke
Ding
,
Xiaoyun
Lu
Diamond Proposal Number(s):
[15433]
Open Access
Abstract: Pancreatic cancer is a leading cause of cancer-related death. A series of 2-amino-2, 3-dihydro-1H-indene-5-carboxamide derivatives were designed and synthesized as novel selective DDR1 inhibitors to exhibit promising in vitro and in vivo anti-pancreatic cancer activity. One of the representative compounds, 7f, binds with DDR1 with a Kd value of 5.9 nM and suppresses the kinase activity with an IC50 value of 14.9 nM, but is significantly less potent for majority of a panel of 403 wild-type kinases. The compound potently inhibited collagen-induced epithelial-mesenchymal transition (EMT) and dose-dependently suppressed colony formation of pancreatic cancer cells. Furthermore, 7f also demonstrated reasonable pharmacokinetic profiles and displayed promising in vivo therapeutic efficacy in an orthotopic mouse model of pancreatic cancer. Compound 7f may serve as a new lead compound for future drug discovery.
|
Jul 2019
|
|
I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
|
Philip
Hinchliffe
,
Diego M.
Moreno
,
Maria-Agustina
Rossi
,
Maria F.
Mojica
,
Veronica
Martinez
,
Valentina
Villamil
,
Brad
Spellberg
,
George L.
Drusano
,
Claudia
Banchio
,
Graciela
Mahler
,
Robert A.
Bonomo
,
Alejandro J.
Vila
,
James
Spencer
Diamond Proposal Number(s):
[12342, 17212]
Abstract: Metallo-β-lactamase (MBL) production in Gram-negative bacteria is an important contributor to β-lactam antibiotic resistance. Combining β-lactams with β-lactamase inhibitors (BLIs) is a validated route to overcoming resistance, but MBL inhibitors are not available in the clinic. On the basis of zinc utilization and sequence, MBLs are divided into three subclasses, B1, B2, and B3, whose differing active-site architectures hinder development of BLIs capable of “cross-class” MBL inhibition. We previously described 2-mercaptomethyl thiazolidines (MMTZs) as B1 MBL inhibitors (e.g., NDM-1) and here show that inhibition extends to the clinically relevant B2 (Sfh-I) and B3 (L1) enzymes. MMTZs inhibit purified MBLs in vitro (e.g., Sfh-I, Ki 0.16 μM) and potentiate β-lactam activity against producer strains. X-ray crystallography reveals that inhibition involves direct interaction of the MMTZ thiol with the mono- or dizinc centers of Sfh-I/L1, respectively. This is further enhanced by sulfur-π interactions with a conserved active site tryptophan. Computational studies reveal that the stereochemistry at chiral centers is critical, showing less potent MMTZ stereoisomers (up to 800-fold) as unable to replicate sulfur-π interactions in Sfh-I, largely through steric constraints in a compact active site. Furthermore, in silico replacement of the thiazolidine sulfur with oxygen (forming an oxazolidine) resulted in less favorable aromatic interactions with B2 MBLs, though the effect is less than that previously observed for the subclass B1 enzyme NDM-1. In the B3 enzyme L1, these effects are offset by additional MMTZ interactions with the protein main chain. MMTZs can therefore inhibit all MBL classes by maintaining conserved binding modes through different routes.
|
Aug 2021
|
|
Krios I-Titan Krios I at Diamond
|
Pu
Qian
,
Alastair T.
Gardiner
,
Ivana
Šímová
,
Katerina
Naydenova
,
Tristan I.
Croll
,
Philip J.
Jackson
,
Nupur
Nupur
,
Miroslav
Kloz
,
Petra
Čubáková
,
Marek
Kuzma
,
Yonghui
Zeng
,
Pablo
Castro-Hartmann
,
Bart
Van Knippenberg
,
Kenneth N.
Goldie
,
David
Kaftan
,
Pavel
Hrouzek
,
Jan
Hájek
,
Jon
Agirre
,
C. Alistair
Siebert
,
David
Bína
,
Kasim
Sader
,
Henning
Stahlberg
,
Roman
Sobotka
,
Christopher J.
Russo
,
Tomáš
Polívka
,
C. Neil
Hunter
,
Michal
Koblížek
Diamond Proposal Number(s):
[29785]
Open Access
Abstract: Phototrophic Gemmatimonadetes evolved the ability to use solar energy following horizontal transfer of photosynthesis-related genes from an ancient phototrophic proteobacterium. The electron cryo-microscopy structure of the Gemmatimonas phototrophica photosystem at 2.4 Å reveals a unique, double-ring complex. Two unique membrane-extrinsic polypeptides, RC-S and RC-U, hold the central type 2 reaction center (RC) within an inner 16-subunit light-harvesting 1 (LH1) ring, which is encircled by an outer 24-subunit antenna ring (LHh) that adds light-gathering capacity. Femtosecond kinetics reveal the flow of energy within the RC-dLH complex, from the outer LHh ring to LH1 and then to the RC. This structural and functional study shows that G. phototrophica has independently evolved its own compact, robust, and highly effective architecture for harvesting and trapping solar energy.
|
Feb 2022
|
|
|
|
Nuria
Tapia-Ruiz
,
A. Robert
Armstrong
,
Hande
Alptekin
,
Marco A.
Amores
,
Heather
Au
,
Jerry
Barker
,
Rebecca
Boston
,
William R
Brant
,
Jake M.
Brittain
,
Yue
Chen
,
Manish
Chhowalla
,
Yong-Seok
Choi
,
Sara I. R.
Costa
,
Maria
Crespo Ribadeneyra
,
Serena A
Cussen
,
Edmund J.
Cussen
,
William I. F.
David
,
Aamod V
Desai
,
Stewart A. M.
Dickson
,
Emmanuel I.
Eweka
,
Juan D.
Forero-Saboya
,
Clare
Grey
,
John M.
Griffin
,
Peter
Gross
,
Xiao
Hua
,
John T. S.
Irvine
,
Patrik
Johansson
,
Martin O.
Jones
,
Martin
Karlsmo
,
Emma
Kendrick
,
Eunjeong
Kim
,
Oleg V
Kolosov
,
Zhuangnan
Li
,
Stijn F L
Mertens
,
Ronnie
Mogensen
,
Laure
Monconduit
,
Russell E
Morris
,
Andrew J.
Naylor
,
Shahin
Nikman
,
Christopher A
O’keefe
,
Darren M. C.
Ould
,
Robert G.
Palgrave
,
Philippe
Poizot
,
Alexandre
Ponrouch
,
Stéven
Renault
,
Emily M.
Reynolds
,
Ashish
Rudola
,
Ruth
Sayers
,
David O.
Scanlon
,
S.
Sen
,
Valerie R.
Seymour
,
Begoña
Silván
,
Moulay Tahar
Sougrati
,
Lorenzo
Stievano
,
Grant S.
Stone
,
Chris I.
Thomas
,
Maria-Magdalena
Titirici
,
Jincheng
Tong
,
Thomas J.
Wood
,
Dominic S
Wright
,
Reza
Younesi
Open Access
Abstract: Increasing concerns regarding the sustainability of lithium sources, due to their limited availability and consequent expected price increase, have raised awareness of the importance of developing alternative energy-storage candidates that can sustain the ever-growing energy demand. Furthermore, limitations on the availability of the transition metals used in the manufacturing of cathode materials, together with questionable mining practices, are driving development towards more sustainable elements. Given the uniformly high abundance and cost-effectiveness of sodium, as well as its very suitable redox potential (close to that of lithium), sodium-ion battery technology offers tremendous potential to be a counterpart to lithium-ion batteries (LIBs) in different application scenarios, such as stationary energy storage and low-cost vehicles. This potential is reflected by the major investments that are being made by industry in a wide variety of markets and in diverse material combinations. Despite the associated advantages of being a drop-in replacement for LIBs, there are remarkable differences in the physicochemical properties between sodium and lithium that give rise to different behaviours, for example, different coordination preferences in compounds, desolvation energies, or solubility of the solid–electrolyte interphase inorganic salt components. This demands a more detailed study of the underlying physical and chemical processes occurring in sodium-ion batteries and allows great scope for groundbreaking advances in the field, from lab-scale to scale-up. This roadmap provides an extensive review by experts in academia and industry of the current state of the art in 2021 and the different research directions and strategies currently underway to improve the performance of sodium-ion batteries. The aim is to provide an opinion with respect to the current challenges and opportunities, from the fundamental properties to the practical applications of this technology.
|
Jul 2021
|
|
Theoretical Physics
|
Abstract: A historical overview of magnetic x-ray dichroism is presented. I describe the first theoretical and experimental results that have led to the development of this powerful technique for element-specific magnetometry. The theoretical progress of the sum rules is also described, starting with the spinorbit sum rule for the isotropic spectrum which led on to the spin and orbital moment sum rules for x-ray magnetic circular dichroism. The latter has been particularly useful to understand the magnetic anisotropy in thin films and multilayers. Further developments of circular dichroism in (resonant) photoemission and Auger, as well as x-ray detected optical activity, also are summarized. Currently, magnetic x-ray dichroism finds a wide application in x-ray spectroscopy and imaging for the study of magnetic materials and it is considered to be one of the most important discoveries in the field of magnetism in the last few decennia. It is hard to imagine modern research into magnetism without the aid of polarized x-rays.
|
Nov 2013
|
|
I19-Small Molecule Single Crystal Diffraction
|
Diamond Proposal Number(s):
[10344]
Abstract: The hexapodal ligand hexakis(isonicotinoyl)cyclotricatechylene (L1) belonging to the cyclotriveratrylene family of host-molecules has been synthesised and used in the assembly of a series of coordination polymer materials with Re(I), Co(II), Cu(II), Ni(II) and Ag(I) salts. Single crystal structures of the coordination polymers [Re3(L1)2Br3(CO)3] 1, and an isomorphic [M3L2] series where M = Co, Cu or Ni, reveal 2D framework structures with a simplified topology of 36 or hxl. These are composed of M6(L1)2 metallo-cages linked together in a pair-wise fashion through each metal centre. Compound 1 is a rare example of a rhenium coordination polymer and was investigated for guest uptake from solution, complexing I2. The mixed-ligand species [Cu2(L1)(CF3CO2)3(isonicotinate)] forms a (3,4,5)-connected 2D coordination polymer, while [Ag2(L1)(DMF)2]·2BF4·2(H2O)·6(DMF) features a 2D network of (3,6)-connectivity and with kagome dual (kgd) topology.
|
Jun 2018
|
|
Theoretical Physics
|
Frank M. F.
De Groot
,
Hebatalla
Elnaggar
,
Federica
Frati
,
Ru-Pan
Wang
,
Mario U.
Delgado-Jaime
,
Michel
Van Veenendaal
,
Javier
Fernandez-Rodriguez
,
Maurits W.
Haverkort
,
Robert J.
Green
,
Gerrit
Van Der Laan
,
Yaroslav
Kvashnin
,
Atsushi
Hariki
,
Hidekazu
Ikeno
,
Harry
Ramanantoanina
,
Claude
Daul
,
Bernard
Delley
,
Michael
Odelius
,
Marcus
Lundberg
,
Oliver
Kuhn
,
Sergey I.
Bokarev
,
Eric
Shirley
,
John
Vinson
,
Keith
Gilmore
,
Mauro
Stener
,
Giovanna
Fronzoni
,
Piero
Decleva
,
Peter
Kruger
,
Marius
Retegan
,
Yves
Joly
,
Christian
Vorwerk
,
Claudia
Draxl
,
John
Rehr
,
Arata
Tanaka
Open Access
Abstract: This review provides an overview of the different methods and computer codes that are used to interpret 2p x-ray absorption spectra of 3d transition metal ions. We first introduce the basic parameters and give an overview of the methods used. We start with the semi-empirical multiplet codes and compare the different codes that are available. A special chapter is devoted to the user friendly interfaces that have been written on the basis of these codes. Next we discuss the first principle codes based on band structure, including a chapter on Density Functional theory based approaches. We also give an overview of the first-principle multiplet codes that start from a cluster calculation and we discuss the wavefunction based methods, including multi-reference methods. We end the review with a discussion of the link between theory and experiment and discuss the open issues in the spectral analysis.
|
Apr 2021
|
|
I04-Macromolecular Crystallography
|
Open Access
Abstract: The determination of distances between specific points in nucleic acids is essential to understanding their behaviour at the molecular level. The ability to measure distances of 2–10 nm is particularly important: deformations arising from protein binding commonly fall within this range, but the reliable measurement of such distances for a conformational ensemble remains a significant challenge. Using several techniques, we show that electron paramagnetic resonance (EPR) spectroscopy of oligonucleotides spin-labelled with triazole-appended nitroxides at the 2′ position offers a robust and minimally perturbing tool for obtaining such measurements. For two nitroxides, we present results from EPR spectroscopy, X-ray crystal structures of B-form spin-labelled DNA duplexes, molecular dynamics simulations and nuclear magnetic resonance spectroscopy. These four methods are mutually supportive, and pinpoint the locations of the spin labels on the duplexes. In doing so, this work establishes 2′-alkynyl nitroxide spin-labelling as a minimally perturbing method for probing DNA conformation.
|
Feb 2020
|
|
I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
|
Diamond Proposal Number(s):
[7299]
Open Access
Abstract: Retroviral integrase (IN) is responsible for two consecutive reactions, which lead to insertion of a viral DNA copy into a host cell chromosome. Initially, the enzyme removes di‐ or trinucleotides from viral DNA ends to expose 3′‐hydroxyls attached to the invariant CA dinucleotides (3′‐processing reaction). Second, it inserts the processed 3′‐viral DNA ends into host chromosomal DNA (strand transfer). Herein, we report a crystal structure of prototype foamy virus IN bound to viral DNA prior to 3′‐processing. Furthermore, taking advantage of its dependence on divalent metal ion cofactors, we were able to freeze trap the viral enzyme in its ground states containing all the components necessary for 3′‐processing or strand transfer. Our results shed light on the mechanics of retroviral DNA integration and explain why HIV IN strand transfer inhibitors are ineffective against the 3′‐processing step of integration. The ground state structures moreover highlight a striking substrate mimicry utilized by the inhibitors in their binding to the IN active site and suggest ways to improve upon this clinically relevant class of small molecules.
|
May 2012
|
|
