Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry

Joanna Toporowska, Parth Kapoor, Maria Musgaard, Karolina Gherbi, Kathy Sengmany, Feng Qu, Mark Soave, Hsin-Yung Yen, Kjetil Hansen, Ali Jazayeri, Jonathan T. S. Hopper () and Argyris Politis ()
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Joanna Toporowska: King’s College London
Parth Kapoor: OMass Therapeutics
Maria Musgaard: OMass Therapeutics
Karolina Gherbi: OMass Therapeutics
Kathy Sengmany: OMass Therapeutics
Feng Qu: OMass Therapeutics
Mark Soave: OMass Therapeutics
Hsin-Yung Yen: OMass Therapeutics
Kjetil Hansen: King’s College London
Ali Jazayeri: OMass Therapeutics
Jonathan T. S. Hopper: OMass Therapeutics
Argyris Politis: King’s College London

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract G Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development. Here, we use Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) to explore the structural dynamics of the turkey β1-adrenergic receptor (tβ1AR) bound with nine different ligands, including agonists, partial agonists, and antagonists. We find that these ligands induce distinct dynamic patterns across the receptor, which can be grouped by compound modality. Notably, full agonist binding destabilises the intracellular loop 1 (ICL1), while antagonist binding stabilises it, highlighting ICL1’s role in G protein recruitment. Our findings indicate that the conserved L72 residue in ICL1 is crucial for maintaining receptor structural integrity and stabilising the GDP-bound state. Overall, our results provide a platform for determining drug modality and highlight how HDX-MS can be used to dissect receptor ligand interaction properties and GPCR mechanism.

Date: 2024
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DOI: 10.1038/s41467-024-53161-0

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