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Journal Articles eLife Year : 2017

Optocontrol of glutamate receptor activity by single side-chain photoisomerization

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Abstract

Engineering light-sensitivity into proteins has wide ranging applications in molecular studies and neuroscience. Commonly used tethered photoswitchable ligands, however, require solvent-accessible protein labeling, face structural constrains, and are bulky. Here, we designed a set of optocontrollable NMDA receptors by directly incorporating single photoswitchable amino acids (PSAAs) providing genetic encodability, reversibility, and site tolerance. We identified several positions within the multi-domain receptor endowing robust photomodulation. PSAA photoisomerization at the GluN1 clamshell hinge is sufficient to control glycine sensitivity and activation efficacy. Strikingly, in the pore domain, flipping of a M3 residue within a conserved transmembrane cavity impacts both gating and permeation properties. Our study demonstrates the first detection of molecular rearrangements in real-time due to the reversible light-switching of single amino acid side-chains, adding a dynamic dimension to protein site-directed mutagenesis. This novel approach to interrogate neuronal protein function has general applicability in the fast expanding field of optopharmacology.
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Dates and versions

inserm-02439004 , version 1 (14-01-2020)

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Viktoria Klippenstein, Christian Hoppmann, Shixin Ye, Lei Wang, Pierre Paoletti. Optocontrol of glutamate receptor activity by single side-chain photoisomerization. eLife, 2017, 6, pp.e25808. ⟨10.7554/eLife.25808⟩. ⟨inserm-02439004⟩
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