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Side‐chain dynamics of the α$_{1B}$ ‐adrenergic receptor determined by NMR via methyl relaxation

Baumann, Christian; Chiang, Wan‐Chin; Valsecchi, Renato; Jurt, Simon; Deluigi, Mattia; Schuster, Matthias; Rosengren, Karl Johan; Plückthun, Andreas; Zerbe, Oliver (2023). Side‐chain dynamics of the α$_{1B}$ ‐adrenergic receptor determined by NMR via methyl relaxation. Protein Science, 32(11):e4801.

Abstract

G protein‐coupled receptors (GPCRs) are medically important membrane proteins that sample inactive, intermediate, and active conformational states characterized by relatively slow interconversions (~μs–ms). On a faster timescale (~ps–ns), the conformational landscape of GPCRs is governed by the rapid dynamics of amino acid side chains. Such dynamics are essential for protein functions such as ligand recognition and allostery. Unfortunately, technical challenges have almost entirely precluded the study of side‐chain dynamics for GPCRs. Here, we investigate the rapid side‐chain dynamics of a thermostabilized α$_{1B}$‐adrenergic receptor (α$_{1B}$‐AR) as probed by methyl relaxation. We determined order parameters for Ile, Leu, and Val methyl groups in the presence of inverse agonists that bind orthosterically (prazosin, tamsulosin) or allosterically (conopeptide ρ‐TIA). Despite the differences in the ligands, the receptor's overall side‐chain dynamics are very similar, including those of the apo form. However, ρ‐TIA increases the flexibility of Ile176$^{4×56}$ and possibly of Ile214$^{5×49}$, adjacent to Pro215$^{5×50}$ of the highly conserved P$^{5×50}$I$^{3×40}$F$^{6×44}$ motif crucial for receptor activation, suggesting differences in the mechanisms for orthosteric and allosteric receptor inactivation. Overall, increased Ile side‐chain rigidity was found for residues closer to the center of the membrane bilayer, correlating with denser packing and lower protein surface exposure. In contrast to two microbial membrane proteins, in α$_{1B}$‐AR Leu exhibited higher flexibility than Ile side chains on average, correlating with the presence of Leu in less densely packed areas and with higher protein‐surface exposure than Ile. Our findings demonstrate the feasibility of studying receptor‐wide side‐chain dynamics in GPCRs to gain functional insights.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
540 Chemistry
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Uncontrolled Keywords:Molecular Biology, Biochemistry, GPCR, activation
Language:English
Date:1 November 2023
Deposited On:13 Nov 2023 15:55
Last Modified:26 Sep 2024 03:38
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0961-8368
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/pro.4801
PubMed ID:37805830
Project Information:
  • Funder: Schweizer Nationalfond
  • Grant ID: 310030-19767
  • Project Title:
  • Funder: Schweizer Nationalfond
  • Grant ID: 310030-15945
  • Project Title:
  • Funder: Forschungskredit
  • Grant ID: K-18-083
  • Project Title:
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

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