Thermodynamic architecture and conformational plasticity of GPCRs

Sathvik Anantakrishnan and Athi N. Naganathan ()
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Sathvik Anantakrishnan: Indian Institute of Technology Madras
Athi N. Naganathan: Indian Institute of Technology Madras

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract G-protein-coupled receptors (GPCRs) are ubiquitous integral membrane proteins involved in diverse cellular signaling processes. Here, we carry out a large-scale ensemble thermodynamic study of 45 ligand-free GPCRs employing a structure-based statistical mechanical framework. We find that multiple partially structured states co-exist in the GPCR native ensemble, with the TM helices 1, 6 and 7 displaying varied folding status, and shaping the conformational landscape. Strongly coupled residues are anisotropically distributed, accounting for only 13% of the residues, illustrating that a large number of residues are inherently dynamic. Active-state GPCRs are characterized by reduced conformational heterogeneity with altered coupling-patterns distributed throughout the structural scaffold. In silico alanine-scanning mutagenesis reveals that extra- and intra-cellular faces of GPCRs are coupled thermodynamically, highlighting an exquisite structural specialization and the fluid nature of the intramolecular interaction network. The ensemble-based perturbation methodology presented here lays the foundation for understanding allosteric mechanisms and the effects of disease-causing mutations in GCPRs.

Date: 2023
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DOI: 10.1038/s41467-023-35790-z

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