9EGM

Human BEST1 bound to GABA in an open state

Summary for 9EGM

• Entry DOI: 10.2210/pdb9egm/pdb
• Related: 9EFZ 9EGQ 9EGS 9EGT
• EMDB information: 47991
• Descriptor: Bestrophin-1, CHLORIDE ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: bestrophin, ion channel, gaba, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 237975.50

Authors

Pant, S.,Long, S.B. (deposition date: 2024-11-21, release date: 2025-04-09, Last modification date: 2025-05-14)

Primary citation

Pant, S.,Tam, S.W.,Long, S.B.
The pentameric chloride channel BEST1 is activated by extracellular GABA.
Proc.Natl.Acad.Sci.USA, 122:e2424474122-e2424474122, 2025

PubMed Abstract: Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter -aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA G-protein-coupled receptors and the pentameric GABA chloride channels, both of which have fundamental roles in the central nervous system. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel's extracellular side and determine the mechanism by which GABA binding stabilizes opening of the channel's central gate. This same gate, "the neck," is activated by intracellular [Ca], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.

PubMed: 40249777
DOI: 10.1073/pnas.2424474122

Experimental method

ELECTRON MICROSCOPY (2.45 Å)