A Functionally Conserved Mechanism of Modulation via a Vestibule Site in Pentameric Ligand-Gated Ion Channels
A Functionally Conserved Mechanism of Modulation via a Vestibule Site in Pentameric Ligand-Gated Ion Channels
ABSTRACT Pentameric ligand-gated ion channels (pLGICs) belong to a class of ion channels involved in fast synaptic signaling in the central and peripheral nervous systems. Molecules acting as allosteric modulators target binding sites that are remote from the neurotransmitter binding site, but functionally affect coupling of ligand binding to channel opening. Here, we investigated an allosteric binding site in the ion channel vestibule, which has converged from a series of studies on prokaryote and eukaryote channel homologs. We discovered single domain antibodies, called nanobodies, which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote channel ELIC bound either to a positive (PAM) or a negative (NAM) allosteric modulator. We extrapolate the functional importance of the vestibule binding site to eukaryote ion channels, suggesting a conserved mechanism of allosteric modulation. This work identifies key elements of allosteric binding sites and extends drug design possibilities in pLGICs using nanobodies.
Govaerts Cedric、Price Kerry、Pardon Els、Hibbs Ryan E.、Gharpure Anant、Kambara Kumiko、Ulens Chris、Bertrand Daniel、Lummis Sarah C. R.、Brams Marijke、Spurny Radovan、Steyaert Jan、Evans Genevieve L.
Laboratory for the Structure and Function of Biological Membranes, Center for Structural Biology and Bioinformatics, Universit¨| libre de BruxellesDepartment of Biochemistry, University of CambridgeStructural Biology Brussels, Vrije Universiteit Brussel||VIB-VUB Center for Structural BiologyDepartments of Neuroscience and Biophysics, University of Texas Southwestern Medical CenterDepartments of Neuroscience and Biophysics, University of Texas Southwestern Medical CenterHiQscreen, 1222 V¨|senazLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of MedicineHiQscreen, 1222 V¨|senazDepartment of Biochemistry, University of CambridgeLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of MedicineLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of MedicineStructural Biology Brussels, Vrije Universiteit Brussel||VIB-VUB Center for Structural BiologyLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine
基础医学生物科学现状、生物科学发展生物科学研究方法、生物科学研究技术
Govaerts Cedric,Price Kerry,Pardon Els,Hibbs Ryan E.,Gharpure Anant,Kambara Kumiko,Ulens Chris,Bertrand Daniel,Lummis Sarah C. R.,Brams Marijke,Spurny Radovan,Steyaert Jan,Evans Genevieve L..A Functionally Conserved Mechanism of Modulation via a Vestibule Site in Pentameric Ligand-Gated Ion Channels[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/770719.点此复制
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