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Updated: Jun 29, 2025
High-throughput Analysis of Mammalian Olfactory Receptors: Measurement of Receptor Activation via Luciferase Activity
Published on: June 2, 2014
Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor
Lorenza Pirona1, Federico Ballabio1, Mercedes Alfonso-Prieto2
1Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, I-20133 Milano, Italy.
Abstract:
Conformational changes as well as molecular determinants related to the activation and inactivation of olfactory receptors are still poorly understood due to the intrinsic difficulties in the structural determination of this GPCR family. Here, we perform, for the first time, the in silico inactivation of human olfactory receptor OR51E2, highlighting the possible role of calcium in this receptor state transition. Using molecular dynamics simulations, we show that a divalent ion in the ion binding site, coordinated by two acidic residues at positions 2.50 and 3.39 conserved across most ORs, stabilizes the receptor in its inactive state. In contrast, protonation of the same two acidic residues is not sufficient to drive inactivation within the microsecond timescale of our simulations. Our findings suggest a novel molecular mechanism for OR inactivation, potentially guiding experimental validation and offering insights into the possible broader role of divalent ions in GPCR signaling.
Insights
Divalent ions, like calcium, may stabilize olfactory receptors (ORs) in an inactive state. This study used computational methods to reveal a potential new mechanism for OR inactivation, offering insights into GPCR signaling.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Olfactory receptors (ORs), a family of G protein-coupled receptors (GPCRs), play a crucial role in smell perception.
- Understanding the structural basis of OR activation and inactivation is challenging due to difficulties in their structural determination.
- The molecular mechanisms governing OR inactivation remain poorly understood.
Purpose of the Study:
- To investigate the molecular determinants and mechanisms underlying the inactivation of the human olfactory receptor OR51E2.
- To explore the potential role of calcium ions in the inactivation process of OR51E2.
- To elucidate a novel mechanism for GPCR inactivation using computational approaches.
Main Methods:
- In silico inactivation of human olfactory receptor OR51E2 using molecular dynamics simulations.
- Analysis of ion binding sites and conserved acidic residues (at positions 2.50 and 3.39) within the receptor.
- Comparison of the effects of divalent ion binding versus protonation on receptor stability.
Main Results:
- A divalent ion, potentially calcium, in the ion binding site stabilizes OR51E2 in its inactive conformation.
- This stabilization is mediated by coordination with two conserved acidic residues at positions 2.50 and 3.39.
- Protonation of these acidic residues alone was insufficient to induce inactivation within the simulated timescale.
Conclusions:
- Divalent ions play a significant role in stabilizing olfactory receptors in an inactive state.
- A novel molecular mechanism for OR inactivation involving divalent ion coordination is proposed.
- These findings provide insights into GPCR signaling and may guide future experimental validation.
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