TY  - JOUR
AU  - Pirona, Lorenza
AU  - Ballabio, Federico
AU  - Alfonso-Prieto, Mercedes
AU  - Capelli, Riccardo
TI  - Calcium-Driven In Silico Inactivation of a Human Olfactory Receptor
JO  - Journal of chemical information and modeling
VL  - 64
IS  - 8
SN  - 1549-9596
CY  - Washington, DC
PB  - American Chemical Society
M1  - FZJ-2024-02081
SP  - 2971–2978
PY  - 2024
N1  - Preprint available at bioRxiv: https://doi.org/10.1101/2024.01.31.578070. Enclosed you can find the author's version of the main text and SI submitted right before acceptance by the journal.
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 38523266
UR  - <Go to ISI:>//WOS:001190706500001
DO  - DOI:10.1021/acs.jcim.4c00249
UR  - https://juser.fz-juelich.de/record/1024274
ER  -