Preprint

FZJ-2024-02364

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Calcium-driven In Silico Inactivation of a Human Olfactory Receptor

Pirona, L. ; Ballabio, F. ; Alfonso-Prieto, M.FZJ* ; Capelli, R. (Corresponding author)

2024
Cold Spring Harbor Laboratory, NY Cold Spring Harbor

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Please use a persistent id in citations: doi:10.1101/2024.01.31.578070  doi:10.34734/FZJ-2024-02364

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 the 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 µs 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.

Note: Preprint publicly available; peer-reviewed version was published in Journal of Chemical Information and Modeling (doi: 10.1021/acs.jcim.4c00249)

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. DFG project 291198853 - FOR 2518: Funktionale Dynamik von Ionenkanälen und Transportern - DynIon - (291198853) (291198853)
3. DFG project 329460521 - Protonentransfer und Substraterkennung in SLC17-Transportern (329460521) (329460521)

Appears in the scientific report 2024

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