ORCID Profile
0000-0001-5583-6460
Current Organisation
University of Oxford
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-07-2022
Abstract: Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.
Publisher: Wiley
Date: 16-05-2018
DOI: 10.1002/MRC.4737
Publisher: Springer Science and Business Media LLC
Date: 18-08-2021
DOI: 10.1038/S41586-021-03825-4
Abstract: ADP-ribosyltransferases use NAD
Publisher: Wiley
Date: 26-09-2018
Abstract: In animals, the response to chronic hypoxia is mediated by upregulation of the α,β-heterodimeric hypoxia-inducible factors (HIFs). Levels of HIFα isoforms, but not HIFβ, are regulated by their post-translational modification as catalysed by prolyl hydroxylase domain enzymes (PHDs). Different roles for the human HIF-1/2α isoforms and their two oxygen-dependent degradation domains (ODDs) are proposed. We report kinetic and NMR analyses of the ODD selectivity of the catalytic domain of wild-type PHD2 (which is conserved in nearly all animals) and clinically observed variants. Studies using Ala scanning and "hybrid" ODD peptides imply that the relatively rigid conformation of the (hydroxylated) proline plays an important role in ODD binding. They also reveal differential roles in binding for the residues on the N- and C-terminal sides of the substrate proline. The overall results indicate how the PHDs achieve selectivity for HIFα ODDs and might be of use in identifying substrate-selective PHD inhibitors.
Publisher: Wiley
Date: 17-09-2019
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Publisher: Wiley
Date: 17-09-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8CC00387D
Abstract: The binding of prolyl-hydroxylated HIF-α to PHD2 is hindered by prior 2OG binding likely, leading to the inhibition of HIF-α degradation under limiting 2OG conditions.
Publisher: American Chemical Society (ACS)
Date: 11-04-2018
DOI: 10.1021/JACS.8B02552
Abstract: We report the template-directed synthesis of a π-conjugated 14-porphyrin nanoball. This structure consists of two intersecting nanorings containing six and 10 porphyrin units. Fluorescence upconversion spectroscopy experiments demonstrate that electronic excitation delocalizes over the whole three-dimensional π system in less than 0.3 ps if the nanoball is bound to its templates or over 2 ps if the nanoball is empty.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Tim Claridge.