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Allosteric coupling of sub-millisecond clamshell motions in ionotropic glutamate receptor ligand-binding domains
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-261678
- Ionotropic glutamate receptors (iGluRs) mediate signal transmission in the brain and are important drug targets. Structural studies show snapshots of iGluRs, which provide a mechanistic understanding of gating, yet the rapid motions driving the receptor machinery are largely elusive. Here we detect kinetics of conformational change of isolated clamshell-shaped ligand-binding domains (LBDs) from the three major iGluR sub-types, which initiate gating upon binding of agonists. We design fluorescence probes to measure domain motions throughIonotropic glutamate receptors (iGluRs) mediate signal transmission in the brain and are important drug targets. Structural studies show snapshots of iGluRs, which provide a mechanistic understanding of gating, yet the rapid motions driving the receptor machinery are largely elusive. Here we detect kinetics of conformational change of isolated clamshell-shaped ligand-binding domains (LBDs) from the three major iGluR sub-types, which initiate gating upon binding of agonists. We design fluorescence probes to measure domain motions through nanosecond fluorescence correlation spectroscopy. We observe a broad kinetic spectrum of LBD dynamics that underlie activation of iGluRs. Microsecond clamshell motions slow upon dimerization and freeze upon binding of full and partial agonists. We uncover allosteric coupling within NMDA LBD hetero-dimers, where binding of L-glutamate to the GluN2A LBD stalls clamshell motions of the glycine-binding GluN1 LBD. Our results reveal rapid LBD dynamics across iGluRs and suggest a mechanism of negative allosteric cooperativity in NMDA receptors.…
Autor(en): | Suhaila Rajab, Leah Bismin, Simone Schwarze, Alexandra Pinggera, Ingo H. Greger, Hannes Neuweiler |
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URN: | urn:nbn:de:bvb:20-opus-261678 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Communications Biology |
Erscheinungsjahr: | 2021 |
Band / Jahrgang: | 4 |
Heft / Ausgabe: | 1 |
Aufsatznummer: | 1056 |
Originalveröffentlichung / Quelle: | Communications Biology (2021) 4:1, 1056. https://doi.org/10.1038/s42003-021-02605-0 |
DOI: | https://doi.org/10.1038/s42003-021-02605-0 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Freie Schlagwort(e): | fluorescence spectroscopy; kinetics; ligand-gated ion channels; molecular neuroscience |
Datum der Freischaltung: | 22.04.2022 |
Open-Access-Publikationsfonds / Förderzeitraum 2021 | |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |