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199 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer’s disease Yuhong Du , William J. Bradshaw , Tina M. Leisner , Joel K. Annor-Gyamfi , Kun Qian , Frances M. Bashore , Arunima Sikdar , Felix O. Nwogbo , Andrey A. Ivanov , Stephen V. Frye , Opher Gileadi , Paul E. Brennan , Allan I. Levey , Alison D. Axtman , Kenneth H. Pearce , Haian Fu , Vittorio L. Katis , Ishita Ajith , Jeff Aube , Ranjita S. Betarbet , Juan Botas , Peter J. Brown , Robert R. Butler , Jacob L. Capener , Gregory W. Carter , Gregory A. Cary , Catherine Chen , Rachel Commander , Sabrina Daglish , Suzanne Doolen , Aled M. Edwards , Michelle E. Etoundi , Kevin J. Frankowski , Marta Glavatshikh , Jake Gockley , Katerina Gospodinova , Anna K. Greenwood , Peter A. Greer , Lea T. Grinberg , Shiva Guduru , Levon Halabelian , Crystal Han , Brian Hardy , Laura M. Heath , Stephanie Howell , Suman Jayadev , Stephen Keegan , May Khanna , Dmitri Kireev , Carl Laflamme , Karina Leal , Tom V. Lee , Qianjin Li , David Li-Kroeger , Zhandong Liu , Benjamin A. Logsdon , Frank M. Longo , Lara M. Mangravite , Peter S. Mcpherson , Richard M. Nwakamma , Carolyn A. Paisie , Arti Parihar , Min Qui , Stacey J. Sukoff Rizzo , Karolina A. Rygiel , Julie Schumacher , David D. Scott , Nicholas T. Seyfried , Joshua M. Shulman , Ben Siciliano , Nathaniel Smith , Michael Stashko , Judith A. Tello Vega , Dilipkumar Uredi , Dongxue Wang , Jianjun Wang , Xiaodong Wang , Zhexing Wen , Jesse C. Wiley , Alexander Wilkes , Charles A. Williams , Timothy M. Willson , Aliza Wingo , Thomas S. Wingo , Novak Yang , Jessica E. Young , Miao Yu , Elizabeth L. Zoeller Journal Of Biological Chemistry 20 DOI: 10.1016/j.jbc.2023.105382 Diamond Proposal Number(s): [19301, 19301] Open Access	Oct 2023
B23-Circular Dichroism	The stabilization of S100A9 structure by calcium inhibits the formation of amyloid fibrils Ella Sanders , Rebecca Csondor , Darius Šulskis , Ieva Baronaitė , Vytautas Smirnovas , Luckshi Maheswaran , Jack Horrocks , Rory Munro , Christina Georgiadou , Istvan Horvath , Ludmilla A. Morozova-Roche , Philip T. F. Williamson International Journal Of Molecular Sciences 24 DOI: 10.3390/ijms241713200 Diamond Proposal Number(s): [19915] Open Access Show Abstract ▼ Abstract: The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-β peptide and α-synuclein in Alzheimer’s and Parkinson’s diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure. The exact mechanism by which calcium exerts its influence on the aggregation process remains unclear. Here we demonstrate that despite S100A9 exhibiting α-helical secondary structure in the absence of calcium, the protein exhibits significant plasticity with interconversion between different conformational states occurring on the micro- to milli-second timescale. This plasticity allows the population of conformational states that favour the onset of fibril formation. Magic-angle spinning solid-state NMR studies of the resulting S100A9 fibrils reveal that the S100A9 adopts a single structurally well-defined rigid fibrillar core surrounded by a shell of approximately 15–20 mobile residues, a structure that persists even when fibrils are produced in the presence of calcium ions. These studies highlight how the dysregulation of metal ion concentrations can influence the conformational equilibria of this important neuroinflammatory protein to influence the rate and nature of the amyloid deposits formed.	Aug 2023
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Discovery of IACS-52825, a potent and selective DLK inhibitor for treatment of chemotherapy-induced peripheral neuropathy Kang Le , Michael J. Soth , Jason B. Cross , Gang Liu , William J. Ray , Jiacheng Ma , Sunil G. Goodwani , Paul J. Acton , Virginie Buggia-Prevot , Onno Akkermans , John Barker , Michael L. Conner , Yongying Jiang , Zhen Liu , Paul Mcewan , Jennifer Warner-Schmidt , Alan Xu , Matthias Zebisch , Cobi J. Heijnen , Brett Abrahams , Philip Jones Journal Of Medicinal Chemistry 27 DOI: 10.1021/acs.jmedchem.3c00788 Diamond Proposal Number(s): [14636, 17183] Show Abstract ▼ Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet medical need with limited treatment options. Despite different mechanisms of action, diverse chemotherapeutics can cause CIPN through a converged pathway─an active axon degeneration program that engages the dual leucine zipper kinase (DLK). DLK is a neuronally enriched kinase upstream in the MAPK-JNK cascade, and while it is dormant under physiological conditions, DLK mediates a core mechanism for neuronal injury response under stress conditions, making it an attractive target for treatment of neuronal injury and neurodegenerative diseases. We have developed potent, selective, brain penetrant DLK inhibitors with excellent PK and activity in mouse models of CIPN. Lead compound IACS-52825 (22) showed strongly effective reversal of mechanical allodynia in a mouse model of CIPN and was advanced into preclinical development.	Jul 2023
I08-Scanning X-ray Microscopy beamline (SXM)	Illuminating the brain: revealing brain biochemistry with synchrotron x-ray spectromicroscopy James Everett , Jake Brooks , Frederik Lermyte , Vindy Tjendana Tjhin , Ian Hands-Portman , Emily Hill , Joanna F. Collingwood , Neil D. Telling Journal Of Electron Spectroscopy And Related Phenomena 14 DOI: 10.1016/j.elspec.2023.147355 Diamond Proposal Number(s): [15230, 24534, 29042, 30776] Open Access Show Abstract ▼ Abstract: The synchrotron x-ray spectromicroscopy technique Scanning Transmission X-ray Microscopy (STXM) offers a powerful means to examine the underlying biochemistry of biological systems, owing to its combined chemical sensitivity and nanoscale spatial resolution. Here we introduce and demonstrate methodology for the use of STXM to examine the biochemistry of the human brain. We then discuss how this approach can help us better understand the biochemical changes that occur during the development of degenerative brain disorders, potentially facilitating the development of new therapies for disease diagnosis and treatment.	Jun 2023
I24-Microfocus Macromolecular Crystallography	The crystal structure of the Hsp90-LA1011 complex and the mechanism by which LA1011 may improve the prognosis of Alzheimer’s disease S. Mark Roe , Zsolt Török , Andrew Mcgown , Ibolya Horváth , John Spencer , Tamás Pázmány , László Vigh , Chrisostomos Prodromou Biomolecules 13 DOI: 10.3390/biom13071051 Diamond Proposal Number(s): [26617] Open Access Show Abstract ▼ Abstract: Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90-dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular, elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90, although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt the binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. However, without direct evidence, we cannot completely rule out effects on other Hsp90-co-chaprone complexes and the mechanisms they are involved in, including effects on Hsp90 client proteins. Nonetheless, it is highly significant that LA1011 showed promise in our previous AD mouse models, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting. The clinical value of LA1011 and its possible derivatives thereof remains to be seen.	Jun 2023
B21-High Throughput SAXS	New approaches to small angle scattering methods for studying α-synuclein and other protein aggregation Han Yin Show Abstract ▼ Abstract: Protein aggregation and amyloidosis are linked to many neurodegenerative diseases as well as rare inherited disorders. Parkinson’s disease in particular, is caused by Lewy bodies – amyloid fibril aggregates of α-synuclein that induce the apoptosis of neuron cells. Although the general amyloid pathway of α-synuclein aggregation has been explored, in-depth structural and kinetic data during each step of aggregation, from monomeric protein to fibrils and propagation, is yet to be fully studied. Due to the disordered nature of α-synuclein monomers and the transient nature of oligomers, the ability to structurally model them has been limited in detail with past techniques such as NMR, CD and light scattering. Despite the current focus on oligomeric aspects of α-synuclein in therapeutics, the seeded aggregation pathway and its prion-like spreading continue to be a crucial area of study. It is evident that the aggregation pathway as a whole should be considered for protein amyloid therapeutics, as each stage is an important conduit to each other, and drug targets can be found at any stage of the aggregation process. However, the constant shift in polydispersity, structure and size during protein aggregation makes it a challenging topic to explore with existing techniques. In the case of α-synuclein, the protein molecule will go through oligomeric, fibril and seeding stages, and even different conformations in the presence or absence of lipids. There has been a gap in the area of amyloids to offer real-time structural data and kinetics in a combined fashion, as well as in-depth structural analysis for disordered monomers and transient oligomers. In this thesis, we aimed to fill the gap in research by using cutting-edge small-angle scattering techniques combined with structural modelling. Chapter 4 and 5 of this thesis will explore the monomeric and oligomeric forms of α-synuclein using SEC-SAXS from Diamond Light Source. Chapter 6 will focus on developing SAXS techniques to study the seeded aggregation pathway of α-synuclein. And finally, Chapter 7 will explore the challenging topic of vesicle induced aggregation using the contrast matching technique of small angle neutron scattering. We hope the thesis will provide the reader novel insights into the aggregation of α-synuclein and illustrate the potential usage of these scattering techniques for other protein aggregation studies.	Jun 2023
Krios IV-Titan Krios IV at Diamond	New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy Yang Yang , Holly J. Garringer , Yang Shi , Sofia Lovestam , Sew Peak-Chew , Xianjun Zhang , Abhay Kotecha , Mehtap Bacioglu , Atsuo Koto , Masaki Takao , Maria Grazia Spillantini , Bernardino Ghetti , Ruben Vidal , Alexey G. Murzin , Sjors H. W. Scheres , Michel Goedert Acta Neuropathologica 26 DOI: 10.1007/s00401-023-02550-8 Diamond Proposal Number(s): [23268] Open Access Show Abstract ▼ Abstract: A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36–100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.	Feb 2023
Krios I-Titan Krios I at Diamond	Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains Yang Yang , Wenjuan Zhang , Alexey G. Murzin , Manuel Schweighauser , Melissa Huang , Sofia Lovestam , Sew Y. Peak-Chew , Takashi Saito , Takaomi C. Saido , Jennifer Macdonald , Isabelle Lavenir , Bernardino Ghetti , Caroline Graff , Amit Kumar , Agneta Nordberg , Michel Goedert , Sjors H. W. Scheres Acta Neuropathologica 65 DOI: 10.1007/s00401-022-02533-1 Diamond Proposal Number(s): [23268] Open Access Show Abstract ▼ Abstract: The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer’s disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12–V40 (human Arctic fold A) and E11–G37 (human Arctic fold B). They have a substructure (residues F20–G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line AppNL−G−F. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (AppNL−G−F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL−G−F murine Arctic fold differs from the human Arctic folds, but shares some substructure.	Jan 2023
I24-Microfocus Macromolecular Crystallography	Discovery and optimization of potent, selective, and brain-penetrant 1-heteroaryl-1H-indazole LRRK2 kinase inhibitors for the treatment of Parkinson’s disease David A. Candito , Vladimir Simov , Anmol Gulati , Solomon Kattar , Ryan W. Chau , Blair T. Lapointe , Joey L. Methot , Duane E. Demong , Thomas H. Graham , Ravi Kurukulasuriya , Mitchell H. Keylor , Ling Tong , Gregori J. Morriello , John J. Acton , Barbara Pio , Weiguo Liu , Jack D. Scott , Michael J. Ardolino , Theodore A. Martinot , Matthew L. Maddess , Xin Yan , Hakan Gunaydin , Rachel L. Palte , Spencer E. Mcminn , Lisa Nogle , Hongshi Yu , Ellen C. Minnihan , Charles A. Lesburg , Ping Liu , Jing Su , Laxminarayan G. Hegde , Lily Y. Moy , Janice D. Woodhouse , Robert Faltus , Tina Xiong , Paul Ciaccio , Jennifer A. Piesvaux , Karin M. Otte , Matthew E. Kennedy , David J. Bennett , Erin F. Dimauro , Matthew J. Fell , Santhosh Neelamkavil , Harold B. Wood , Peter H. Fuller , J. Michael Ellis Journal Of Medicinal Chemistry 65, 16801 - 16817 DOI: 10.1021/acs.jmedchem.2c01605 Show Abstract ▼ Abstract: Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson’s disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3–sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.	Dec 2022
B21-High Throughput SAXS I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structural insights into the contactin 1 - neurofascin 155 adhesion complex Lucas M. P. Chataigner , Christos Gogou , Maurits A. Den Boer , Cátia P. Frias , Dominique M. E. Thies-Weesie , Joke C. M. Granneman , Albert J. R. Heck , Dimphna H. Meijer , Bert J. C. Janssen Nature Communications 13 DOI: 10.1038/s41467-022-34302-9 Diamond Proposal Number(s): [19800] Open Access Show Abstract ▼ Abstract: Cell-surface expressed contactin 1 and neurofascin 155 control wiring of the nervous system and interact across cells to form and maintain paranodal myelin-axon junctions. The molecular mechanism of contactin 1 – neurofascin 155 adhesion complex formation is unresolved. Crystallographic structures of complexed and individual contactin 1 and neurofascin 155 binding regions presented here, provide a rich picture of how competing and complementary interfaces, post-translational glycosylation, splice differences and structural plasticity enable formation of diverse adhesion sites. Structural, biophysical, and cell-clustering analysis reveal how conserved Ig1-2 interfaces form competing heterophilic contactin 1 – neurofascin 155 and homophilic neurofascin 155 complexes whereas contactin 1 forms low-affinity clusters through interfaces on Ig3-6. The structures explain how the heterophilic Ig1-Ig4 horseshoe’s in the contactin 1 – neurofascin 155 complex define the 7.4 nm paranodal spacing and how the remaining six domains enable bridging of distinct intercellular distances.	Nov 2022

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