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001024691 1001_ $$0P:(DE-HGF)0$$aPirona, Lorenza$$b0
001024691 245__ $$aCalcium-driven In Silico Inactivation of a Human Olfactory Receptor
001024691 260__ $$aCold Spring Harbor$$bCold Spring Harbor Laboratory, NY$$c2024
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001024691 500__ $$aPreprint publicly available; peer-reviewed version was published in Journal of Chemical Information and Modeling (doi: 10.1021/acs.jcim.4c00249)
001024691 520__ $$aConformational changes as well as molecular determinants related to the activation and inactivation of olfactory receptors are still poorly understood due to the intrinsic difficulties in the structural determination of this GPCR family. Here, we perform, for the first time, the in silico inactivation of the human olfactory receptor OR51E2, highlighting the possible role of calcium in this receptor state transition. Using molecular dynamics simulations, we show that a divalent ion in the ion binding site, coordinated by two acidic residues at positions 2.50 and 3.39 conserved across most ORs, stabilizes the receptor in its inactive state. In contrast, protonation of the same two acidic residues is not sufficient to drive inactivation within the µs timescale of our simulations. Our findings suggest a novel molecular mechanism for OR inactivation, potentially guiding experimental validation and offering insights into the possible broader role of divalent ions in GPCR signaling.
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001024691 536__ $$0G:(GEPRIS)329460521$$aDFG project 329460521 - Protonentransfer und Substraterkennung in SLC17-Transportern (329460521)$$c329460521$$x2
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001024691 7001_ $$0P:(DE-HGF)0$$aBallabio, Federico$$b1
001024691 7001_ $$0P:(DE-Juel1)169976$$aAlfonso-Prieto, Mercedes$$b2$$ufzj
001024691 7001_ $$0P:(DE-Juel1)174546$$aCapelli, Riccardo$$b3$$eCorresponding author
001024691 773__ $$0PERI:(DE-600)2766415-6$$a10.1101/2024.01.31.578070$$tbioRxiv beta$$y2024
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