Deciphering the allosteric dynamics of GPR120-fatty acid interactions within a bilayer nanogold electrochemical receptor biosensor: the impact of replacing tryptophan 198 with proline.

Authors

Wei Xu, Dan Meng, Ming Li, Qingwei Song, Wenling Wu, Yimeng Bi, Chenyu Xu, Yifei Zhang, Dingqiang Lu

Published in

Biomedical microdevices. Volume 27. Issue 1. Pages 11. Mar 07, 2025. Epub Mar 07, 2025.

Abstract

GPR120 is a free fatty acid receptor capable of signalling excess fatty acids. GPR120 can be activated by various types of free fatty acids, causing intracellular signal transduction and exerting energy regulation, immune homeostasis, and neuronal functions. It has been suggested that Trp198 may be an important residue in the recognition and activation of GPR120 by fatty acid ligands, but direct experimental evidence is lacking. In this study, a GPR120-based bilayer gold nanoparticle biosensor (Trp198→Pro) was constructed by genetically manipulating Trp198 on GPR120 by replacing it with proline for the determination of linkage variability between 14 naturally occurring fatty acid ligands and mutant receptors. The results showed that both before and after amino acid substitution the GPR120 bilayer nanogold receptor sensor responded to all 14 natural fatty acid ligands. And the linkage transformation constants of crotonic acid, dodecanoic acid, oleic acid, linoleic acid, α-linolenic acid, and DHA decreased after Trp198 was replaced by Pro. To further reveal its molecular recognition mechanism, molecular simulation docking experiments were performed on GPR120 and 14 fatty acid ligand compounds before and after amino acid substitutions, respectively. The results showed that before and after the amino acid substitutions, the binding conformational affinity values of GPR120 docked with the ligands were negative, implying that these fatty acid ligands can spontaneously bind to the active pocket of GPR120 without absorbing external energy. Upon replacement of Trp198 by Pro, the active pocket of GPR120 at the optimal docking site with the fatty acid ligand is altered, leading to changes in the amino acid residues that exert the interaction. The above results demonstrate that Trp198 indeed plays an important role in the recognition of fatty acid ligands on GPR120. The present study provides direct quantitative evidence for the roles played by different amino acid residues in receptor-ligand recognition and interaction. At the same time, it provides new ideas for the study of other receptor-ligand-linked metastable mechanisms and kinetic laws.

PMID:
40053188
Bibliographic data and abstract were imported from PubMed on 07 Mar 2025.

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