Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 30, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202205198
Keywords
Charge Transfer States; Fluorescent Probe; GABA-a Receptor; Gabazine; QM; MM
Categories
Funding
- Austrian Science Fund (FWF) [W 1232]
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This study investigates the molecular and electronic mechanism of a fluorescein-based imaging probe that targets the human GABA(A) receptor. The probe undergoes a conformational change upon binding to the receptor, leading to turn-on emission. This effect is only observed for a specific form of the probe, which also exhibits the strongest binding to the GABA(A) receptor.
GABA(A) (gamma-aminobutyric acid type A) receptors are ligand-gated ion channels mediating fast inhibitory transmission in the mammalian brain. Here we report the molecular and electronic mechanism governing the turn-on emission of a fluorescein-based imaging probe able to target the human GABA(A) receptor. Multiscale calculations evidence a drastic conformational change of the probe from folded in solution to extended upon binding to the receptor. Intramolecular pi pi-stacking interactions present in the folded probe are responsible for quenching fluorescence in solution. In contrast, unfolding within the GABA(A) receptor changes the nature of the bright excited state triggering emission. Remarkably, this turn-on effect only manifests for the dianionic prototropic form of the imaging probe, which is found to be the strongest binder to the GABA(A) receptor. This study is expected to assist the design of new photoactivatable screening tools for allosteric modulators of the GABA(A) receptor.
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