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Structure paper

TitleThe pentameric chloride channel BEST1 is activated by extracellular GABA.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 16, Page e2424474122, Year 2025
Publish dateApr 22, 2025
AuthorsSwati Pant / Stephanie W Tam / Stephen B Long /
PubMed AbstractBestrophin-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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:40249777 / PubMed Central
MethodsEM (single particle)
Resolution1.95 - 2.62 Å
Structure data

47982

9efz

EMDB-47982, PDB-9efz:
Chicken BEST1 bound to GABA in an open state
Method: EM (single particle) / Resolution: 1.95 Å

47991

9egm

EMDB-47991, PDB-9egm:
Human BEST1 bound to GABA in an open state
Method: EM (single particle) / Resolution: 2.45 Å

47995

9egq

EMDB-47995, PDB-9egq:
Human BEST1 bound to GABA in an intermediate state
Method: EM (single particle) / Resolution: 2.62 Å

47996

9egs

EMDB-47996, PDB-9egs:
Human BEST1 in an inactivated state
Method: EM (single particle) / Resolution: 2.45 Å

47997

9egt

EMDB-47997, PDB-9egt:
Human BEST1 in an open state
Method: EM (single particle) / Resolution: 2.57 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-CL:
Unknown entry

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM

ChemComp-HOH:
WATER

Source
  • gallus gallus (chicken)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / bestrophin / ion channel / GABA

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