Elucidating the activation mechanism of the proton-sensing GPR68 receptor DOI Open Access
Christos Matsingos,

Lesley A. Howell,

Peter J. McCormick

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 9, 2023

ABSTRACT GPR68 is a proton-sensing G-protein Coupled Receptor (GPCR) involved in variety of physiological processes and disorders including neoplastic pathologies. While few other GPCRs have been shown to be activated by decrease the extracellular pH, molecular mechanism their activation remains largely unknown. In this work, we used combined computational vitro approach provide new insight into receptor. Molecular Dynamics simulations were model changes residue interactions motions triggered pH. Global local rearrangements consistent with partial observed upon protonation inactive state. Selected histidine transmembrane acidic residues found significantly upshifted p K values during simulations, consistently previously hypothesised role through Moreover, novel pairing between region was highlighted both sequence analyses simulation data tested site-directed mutagenesis. At last, identified unknown hydrophobic lock that might stabilise conformation regulate transition active state.g

Language: Английский

Molecular basis of proton sensing by G protein-coupled receptors DOI
Matthew K. Howard, Nick Hoppe, Xi‐Ping Huang

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

8
Molecular basis of proton-sensing by G protein-coupled receptors DOI Creative Commons
Matthew K. Howard, Nick Hoppe, Xi‐Ping Huang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 18, 2024

Abstract Three proton-sensing G protein-coupled receptors (GPCRs), GPR4, GPR65, and GPR68, respond to changes in extracellular pH regulate diverse physiology are implicated a wide range of diseases. A central challenge determining how protons activate these is identifying the set residues that bind protons. Here, we determine structures each receptor understand spatial arrangement putative proton sensing active state. With newly developed deep mutational scanning approach, determined functional importance every residue activation for GPR68 by generating ∼9,500 mutants measuring effects on signaling surface expression. This unbiased screen revealed that, unlike other proton-sensitive cell channels receptors, no single site critical recognition GPR68. Instead, network titratable extend from transmembrane region converge canonical class GPCR motifs GPCRs. More broadly, our approach integrating structure interrogation defines new framework understanding rich complexity signaling. One-sentence summary The protonation networks governing human pH-sensing GPCRs uncovered integrative cryo-EM scanning.

Language: Английский

Citations

9
Proton perception and activation of a proton-sensing GPCR DOI

Li-Nan Chen,

Hui Zhou, Kun Xi

et al.

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

1
Graph‐based algorithms to dissect long‐distance water‐mediated H‐bond networks for conformational couplings in GPCRs DOI Creative Commons
Éva Bertalan, Matthew J. Rodrigues, Gebhard F. X. Schertler

et al.

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: April 18, 2024

Abstract Changes in structure and dynamics elicited by agonist ligand binding at the extracellular side of G protein coupled receptors (GPCRs) must be relayed to cytoplasmic receptors. To decipher role water‐mediated hydrogen‐bond networks this relay mechanism, we have developed graph‐based algorithms analysis methodologies applicable datasets static structures distinct GPCRs. For a reference dataset bovine rhodopsin solved same resolution, show that graph analyses capture internal protein–water network. The extended rhodopsins opioid suggest mechanism whereby inactive place much core network required for long‐distance structural change, with extensive local H‐bond clusters observed high resolution water molecules.

Language: Английский

Citations

3
Elucidating the Activation Mechanism of the Proton-sensing GPR68 Receptor DOI Creative Commons
Christos Matsingos,

Lesley A. Howell,

Peter J. McCormick

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(16), P. 168688 - 168688

Published: June 25, 2024

GPR68 is a proton-sensing G-protein Coupled Receptor (GPCR) involved in variety of physiological processes and disorders including neoplastic pathologies. While few other GPCRs have been shown to be activated by decrease the extracellular pH, molecular mechanism their activation remains largely unknown. In this work, we used combined computational vitro approach provide new insight into receptor. Molecular Dynamics simulations were model changes residue interactions motions triggered pH. Global local rearrangements consistent with partial observed upon protonation inactive state. Selected histidine transmembrane acidic residues found significantly upshifted pKa values during simulations, consistently previously hypothesised role through Moreover, novel pairing between region was highlighted both sequence analyses simulation data tested site-directed mutagenesis. At last, identified unknown hydrophobic lock that might stabilise conformation regulate transition active

Language: Английский

Citations

3
Breaking the one‐site myth: the multifaceted world of proton sensing in GPCRs DOI

Manali Agrawal,

Sunil Kumar Singh, Mithu Baidya

et al.

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: May 26, 2025

Proton‐sensing GPCRs detect extracellular acidification and play a pivotal role in maintaining pH homeostasis, influencing processes such as inflammation, cancer progression, neuropathic pain. While initially believed to rely solely on histidine protonation for activation, emerging evidence suggests that acidic triads, beyond residues, are crucial proton sensing. Variations distribution sequence composition among these receptors point distinct activation mechanisms within the proton‐sensing GPCR family. This Viewpoint consolidates findings from previously published studies explore structural molecular intricacies of recognition, receptor downstream signaling GPCRs. By integrating insights dynamics simulations, evolutionary analysis, studies, functional assays, we highlight complex multifaceted nature Collectively, reveal unrecognized network critical residues sites, reshaping our understanding function. Beyond mechanistic insights, this compilation offers new perspectives targeting pathways therapeutic intervention various diseases.

Language: Английский

Citations

0
Elucidating the activation mechanism of the proton-sensing GPR68 receptor DOI Open Access
Christos Matsingos,

Lesley A. Howell,

Peter J. McCormick

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 9, 2023

ABSTRACT GPR68 is a proton-sensing G-protein Coupled Receptor (GPCR) involved in variety of physiological processes and disorders including neoplastic pathologies. While few other GPCRs have been shown to be activated by decrease the extracellular pH, molecular mechanism their activation remains largely unknown. In this work, we used combined computational vitro approach provide new insight into receptor. Molecular Dynamics simulations were model changes residue interactions motions triggered pH. Global local rearrangements consistent with partial observed upon protonation inactive state. Selected histidine transmembrane acidic residues found significantly upshifted p K values during simulations, consistently previously hypothesised role through Moreover, novel pairing between region was highlighted both sequence analyses simulation data tested site-directed mutagenesis. At last, identified unknown hydrophobic lock that might stabilise conformation regulate transition active state.g

Language: Английский

Citations

2