Structural Evidence for the Binding of Monocarboxylates and Dicarboxylates at Pharmacologically Relevant Extracellular Sites of a Pentameric Ligand-gated Ion Channel

Overview

Journal Acta Crystallogr D Struct Biol

Specialty Biochemistry

Date 2020 Jul 7

PMID 32627739

Citations 3

Authors

Zaineb Fourati

Ludovic Sauguet

Marc Delarue

Affiliations

Soon will be listed here.

Abstract

GLIC is a bacterial homologue of the pentameric ligand-gated ion channels (pLGICs) that mediate the fast chemical neurotransmission of nerve signalling in eukaryotes. Because the activation and allosteric modulation features are conserved among prokaryotic and eukaryotic pLGICs, GLIC is commonly used as a model to study the allosteric transition and structural pharmacology of pLGICs. It has previously been shown that GLIC is inhibited by some carboxylic acid derivatives. Here, experimental evidence for carboxylate binding to GLIC is provided by solving its X-ray structures with a series of monocarboxylate and dicarboxylate derivatives, and two carboxylate-binding sites are described: (i) the `intersubunit' site that partially overlaps the canonical pLGIC orthosteric site and (ii) the `intrasubunit' vestibular site, which is only occupied by a subset of the described derivatives. While the intersubunit site is widely conserved in all pLGICs, the intrasubunit site is only conserved in cationic eukaryotic pLGICs. This study sheds light on the importance of these two extracellular modulation sites as potential drug targets in pLGICs.

Citing Articles

Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment.

Bharambe N, Li Z, Seiferth D, Balakrishna A, Biggin P, Basak S Nat Commun. 2024; 15(1):2967.

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Short-chain mono-carboxylates as negative modulators of allosteric transitions in Gloeobacter violaceus ligand-gated ion channel, and impact of a pre-β5 strand (Loop Ω) double mutation on crotonate, not butyrate effect.

Van Renterghem C, Nemecz A, Medjebeur K, Corringer P Physiol Rep. 2024; 12(3):e15916.

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Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations.

Rovsnik U, Zhuang Y, Forsberg B, Carroni M, Yvonnesdotter L, Howard R Life Sci Alliance. 2021; 4(8).

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