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40 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Structural basis of semaphorin‐plexin cis interaction Daniel Rozbesky , Marieke G. Verhagen , Dimple Karia , Gergely N. Nagy , Luis Alvarez , Ross A Robinson , Karl Harlos , Sergi Padilla‐parra , R. Jeroen Pasterkamp , Edith Y. Jones The Embo Journal 58 DOI: 10.15252/embj.2019102926 Diamond Proposal Number(s): [10627] Open Access Show Abstract ▼ Abstract: Semaphorin ligands interact with plexin receptors to contribute to functions in the development of myriad tissues including neurite guidance and synaptic organisation within the nervous system. Cell‐attached semaphorins interact in trans with plexins on opposing cells, but also in cis on the same cell. The interplay between trans and cis interactions is crucial for the regulated development of complex neural circuitry, but the underlying molecular mechanisms are uncharacterised. We have discovered a distinct mode of interaction through which the Drosophila semaphorin Sema1b and mouse Sema6A mediate binding in cis to their cognate plexin receptors. Our high‐resolution structural, biophysical and in vitro analyses demonstrate that monomeric semaphorins can mediate a distinctive plexin binding mode. These findings suggest the interplay between monomeric vs dimeric states has a hereto unappreciated role in semaphorin biology, providing a mechanism by which Sema6s may balance cis and trans functionalities.	Jun 2020
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Drosophila OTK is a glycosaminoglycan-binding protein with high conformational flexibility Daniel Rozbesky , Jim Monistrol , Vitul Jain , James Hillier , Sergi Padilla-parra , E. Yvonne Jones Structure DOI: 10.1016/j.str.2020.02.008 Diamond Proposal Number(s): [14744] Open Access Show Abstract ▼ Abstract: The transmembrane protein OTK plays an essential role in plexin and Wnt signaling during Drosophila development. We have determined a crystal structure of the last three domains of the OTK ectodomain and found that OTK shows high conformational flexibility resulting from mobility at the interdomain interfaces. We failed to detect direct binding between Drosophila Plexin A (PlexA) and OTK, which was suggested previously. We found that, instead of PlexA, OTK directly binds semaphorin 1a. Our binding analyses further revealed that glycosaminoglycans, heparin and heparan sulfate, are ligands for OTK and thus may play a role in the Sema1a-PlexA axon guidance system.	Mar 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	The antiepileptic drug carbamazepine binds to a novel pocket on the Wnt receptor Frizzled-8 Yuguang Zhao , Jingshan Ren , James Hillier , Weixian Lu , E. Yvonne Jones Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b02020 Diamond Proposal Number(s): [14744] Show Abstract ▼ Abstract: Misregulation of Wnt signalling is common in human cancer. Development of small molecule inhibitors against the Wnt receptor, Frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine (CBZ) to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated CBZ can suppress FZD8 mediated Wnt/β-catenin signalling. We determined the crystal structure of the complex at 1.7Å resolution, which reveals that CBZ binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely-related FZD5 and other FZDs for CBZ binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed CBZ mediated Wnt signalling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term CBZ treatment.	Feb 2020
	Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10 Yuguang Zhao , Daming Zhou , Tao Ni , Dimple Karia , Abhay Kotecha , Xiangxi Wang , Zihe Rao , E. Yvonne Jones , Elizabeth E. Fry , Jingshan Ren , David I. Stuart Nature Communications 11 DOI: 10.1038/s41467-019-13936-2 Open Access Show Abstract ▼ Abstract: Coxsackievirus A10 (CV-A10) is responsible for an escalating number of severe infections in children, but no prophylactics or therapeutics are currently available. KREMEN1 (KRM1) is the entry receptor for the largest receptor-group of hand-foot-and-mouth disease causing viruses, which includes CV-A10. We report here structures of CV-A10 mature virus alone and in complex with KRM1 as well as of the CV-A10 A-particle. The receptor spans the viral canyon with a large footprint on the virus surface. The footprint has some overlap with that seen for the neonatal Fc receptor complexed with enterovirus E6 but is larger and distinct from that of another enterovirus receptor SCARB2. Reduced occupancy of a particle-stabilising pocket factor in the complexed virus and the presence of both unbound and expanded virus particles suggests receptor binding initiates a cascade of conformational changes that produces expanded particles primed for viral uncoating.	Jan 2020
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum Yuguang Zhao , Jingshan Ren , James Hillier , Margaret Jones , Weixian Lu , E. Yvonne Jones Journal Of Pineal Research DOI: 10.1111/jpi.12630 Diamond Proposal Number(s): [16814, 14744] Show Abstract ▼ Abstract: The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high resolution structures (≤ 1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which up-regulation of Wnt signalling may be beneficial.	Dec 2019
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors Benjamin N. Atkinson , David Steadman , William Mahy , Yuguang Zhao , James Sipthorp , Elliott D. Bayle , Fredrik Svensson , George Papageorgiou , Fiona Jeganathan , Sarah Frew , Amy Monaghan , Magda Bictash , E. Yvonne Jones , Paul V. Fish Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.126751 Diamond Proposal Number(s): [14744] Show Abstract ▼ Abstract: The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.	Oct 2019
I24-Microfocus Macromolecular Crystallography	iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition Shuo Chen , Jiale Wu , Shan Zhong , Yuntong Li , Ping Zhang , Jingyi Ma , Jingshan Ren , Yun Tan , Yunhao Wang , Kin Fai Au , Christian Siebold , Gareth L. Bond , Zhu Chen , Min Lu , E. Yvonne Jones , Xin Lu Proceedings Of The National Academy Of Sciences 175 DOI: 10.1073/pnas.1909393116 Open Access Show Abstract ▼ Abstract: The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53–iASPP crystal structure reveals that iASPP displaces the p53 L1 loop—which mediates sequence-specific interactions with the signature-corresponding base—without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF–DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain—except the oncogenic E6 from human papillomaviruses (HPVs)—structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.	Aug 2019
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Diversity of oligomerization in Drosophila semaphorins suggests a mechanism of functional fine-tuning Daniel Rozbesky , Ross A. Robinson , Vitul Jain , Max Renner , Tomas Malinauskas , Karl Harlos , Christian Siebold , E. Yvonne Jones Nature Communications 10 DOI: 10.1038/s41467-019-11683-y Diamond Proposal Number(s): [14744, 10627] Open Access Show Abstract ▼ Abstract: Semaphorin ligands and their plexin receptors are one of the major cell guidance factors that trigger localised changes in the cytoskeleton. Binding of semaphorin homodimer to plexin brings two plexins in close proximity which is a prerequisite for plexin signalling. This model appears to be too simplistic to explain the complexity and functional versatility of these molecules. Here, we determine crystal structures for all members of Drosophila class 1 and 2 semaphorins. Unlike previously reported semaphorin structures, Sema1a, Sema2a and Sema2b show stabilisation of sema domain dimer formation via a disulfide bond. Unexpectedly, our structural and biophysical data show Sema1b is a monomer suggesting that semaphorin function may not be restricted to dimers. We demonstrate that semaphorins can form heterodimers with members of the same semaphorin class. This heterodimerization provides a potential mechanism for cross-talk between different plexins and co-receptors to allow fine-tuning of cell signalling.	Aug 2019
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen Benjamin Nicholas Atkinson , David Steadman , Yuguang Zhao , James Sipthorp , Luca Vecchia , Reinis Reinholds Ruza , Fiona Jeganathan , Georgie Lines , Sarah Frew , Amy Monaghan , Svend Kjaer , Magda Bictash , Yvonne Jones , Paul V. Fish Medchemcomm DOI: 10.1039/C9MD00096H Diamond Proposal Number(s): [16814, 14744] Open Access Show Abstract ▼ Abstract: NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 μM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 μM) and isoquinoline 45 (IC50 0.085 μM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray cocrystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.	Apr 2019
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding Lucy C. Walters , Karl Harlos , Simon Brackenridge , Daniel Rozbesky , Jordan R. Barrett , Vitul Jain , Thomas S. Walter , Chris A. O’callaghan , Persephone Borrow , Mireille Toebes , Scott G. Hansen , Jonah Sacha , Shaheed Abdulhaqq , Justin M. Greene , Klaus Früh , Emily Marshall , Louis J. Picker , E. Yvonne Jones , Andrew J. Mcmichael , Geraldine M. Gillespie Nature Communications 9 DOI: 10.1038/s41467-018-05459-z Diamond Proposal Number(s): [14744] Open Access Show Abstract ▼ Abstract: Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding and CD94/NKG2 receptor engagement, human leucocyte antigen E (HLA-E) reports cellular health to NK cells. Previous studies demonstrated a strong bias for VL9 binding by HLA-E, a preference subsequently supported by structural analyses. However, Mycobacteria tuberculosis (Mtb) infection and Rhesus cytomegalovirus-vectored SIV vaccinations revealed contexts where HLA-E and the rhesus homologue, Mamu-E, presented diverse pathogen-derived peptides to CD8+ T cells, respectively. Here we present crystal structures of HLA-E in complex with HIV and Mtb-derived peptides. We show that despite the presence of preferred primary anchor residues, HLA-E-bound peptides can adopt alternative conformations within the peptide binding groove. Furthermore, combined structural and mutagenesis analyses illustrate a greater tolerance for hydrophobic and polar residues in the primary pockets than previously appreciated. Finally, biochemical studies reveal HLA-E peptide binding and exchange characteristics with potential relevance to its alternative antigen presenting function in vivo.	Aug 2018

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