Transient Structural Dynamics of Glycogen Phosphorylase from Nonequilibrium Hydrogen/Deuterium-Exchange Mass Spectrometry
dc.contributor.author | Kish, M | |
dc.contributor.author | Ivory, DP | |
dc.contributor.author | Phillips, JJ | |
dc.date.accessioned | 2024-01-08T09:45:57Z | |
dc.date.issued | 2023-12-29 | |
dc.date.updated | 2024-01-05T12:08:32Z | |
dc.description.abstract | It remains a major challenge to ascertain the specific structurally dynamic changes that underpin protein functional switching. There is a growing need in molecular biology and drug discovery to complement structural models with the ability to determine the dynamic structural changes that occur as these proteins are regulated and function. The archetypal allosteric enzyme glycogen phosphorylase is a clinical target of great interest to treat type II diabetes and metastatic cancers. Here, we developed a time-resolved nonequilibrium millisecond hydrogen/deuterium-exchange mass spectrometry (HDX-MS) approach capable of precisely locating dynamic structural changes during allosteric activation and inhibition of glycogen phosphorylase. We resolved obligate transient changes in the localized structure that are absent when directly comparing active/inactive states of the enzyme and show that they are common to allosteric activation by AMP and inhibition by caffeine, operating at different sites. This indicates that opposing allosteric regulation by inhibitor and activator ligands is mediated by pathways that intersect with a common structurally dynamic motif. This mass spectrometry approach uniquely stands to discover local transient structural dynamics and could be used broadly to identify features that influence the structural transitions of proteins. | en_GB |
dc.description.sponsorship | UKRI | en_GB |
dc.description.sponsorship | Biotechnology and Biological Sciences Research Council (BBSRC) | en_GB |
dc.identifier.citation | Published online 29 December 2023 | en_GB |
dc.identifier.doi | https://doi.org/10.1021/jacs.3c08934 | |
dc.identifier.grantnumber | MR/T02223X/1 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/134923 | |
dc.identifier | ORCID: 0000-0002-5361-9582 (Phillips, Jonathan J) | |
dc.language.iso | en | en_GB |
dc.publisher | American Chemical Society (ACS) | en_GB |
dc.rights | © 2023 The Authors. Open access. Published by American Chemical Society. This publication is licensed under CC-BY 4.0. | en_GB |
dc.title | Transient Structural Dynamics of Glycogen Phosphorylase from Nonequilibrium Hydrogen/Deuterium-Exchange Mass Spectrometry | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2024-01-08T09:45:57Z | |
dc.identifier.issn | 0002-7863 | |
dc.description | This is the final version. Available on open access from the American Chemical Society via the DOI in this record | en_GB |
dc.description | Data Availability: The authors declare that the data supporting the findings of this study are available in this paper and its Supporting Information files. All additional data is available upon reasonable request. Source data are provided with this paper. | en_GB |
dc.identifier.eissn | 1520-5126 | |
dc.identifier.journal | Journal of the American Chemical Society | en_GB |
dc.relation.ispartof | Journal of the American Chemical Society | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2023-12-13 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2023-12-29 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2024-01-08T09:43:49Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2024-01-08T09:46:00Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2023-12-29 |
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Except where otherwise noted, this item's licence is described as © 2023 The Authors. Open access. Published by American Chemical Society. This publication is licensed under CC-BY 4.0.