Crystal Structures of a GABA-receptor Chimera Reveal New Endogenous Neurosteroid-binding Sites

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2017 Oct 3

PMID 28967882

Citations 105

Authors

Duncan Laverty

Philip Thomas

Martin Field

Ole J Andersen

Matthew G Gold

Philip C Biggin

Marc Gielen

Trevor G Smart

Affiliations

Soon will be listed here.

Abstract

γ-Aminobutyric acid receptors (GABARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABARs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABAR function requires high-resolution structures. Here we present the first atomic structures of a GABAR chimera at 2.8-Å resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABARs in neurological disorders.

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