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TitleNeurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10766, Year 2024
Publish dateDec 30, 2024
AuthorsAaron P Owji / Jingyun Dong / Alec Kittredge / Jiali Wang / Yu Zhang / Tingting Yang /
PubMed AbstractBest1 and Best2 are two members of the bestrophin family of anion channels critically involved in the prevention of retinal degeneration and maintenance of intraocular pressure, respectively. Here, ...Best1 and Best2 are two members of the bestrophin family of anion channels critically involved in the prevention of retinal degeneration and maintenance of intraocular pressure, respectively. Here, we solved glutamate- and γ-aminobutyric acid (GABA)-bound Best2 structures, which delineate an intracellular glutamate binding site and an extracellular GABA binding site on Best2, respectively, identified extracellular GABA as a permeable activator of Best2, and elucidated the co-regulation of Best2 by glutamate, GABA and glutamine synthetase in vivo. We further identified multiple small molecules as activators of the bestrophin channels. Extensive analyses were carried out for a potent activator, 4-aminobenzoic acid (PABA): PABA-bound Best1 and Best2 structures are solved and illustrate the same binding site as in GABA-bound Best2; PABA treatment rescues the functional deficiency of patient-derived Best1 mutations. Together, our results demonstrate the mechanism and potential of multiple small molecule candidates as clinically applicable drugs for bestrophin-associated diseases/conditions.
External linksNat Commun / PubMed:39737942 / PubMed Central
MethodsEM (single particle)
Resolution2.27 - 3.15 Å
Structure data

47304

9dyh

EMDB-47304, PDB-9dyh:
BEST2 + glutamate open state
Method: EM (single particle) / Resolution: 3.15 Å

47305

9dyi

EMDB-47305, PDB-9dyi:
BEST2 + glutamate closed state
Method: EM (single particle) / Resolution: 3.03 Å

47306

9dyj

EMDB-47306, PDB-9dyj:
BEST2 + GABA open state
Method: EM (single particle) / Resolution: 2.31 Å

47307

9dyk

EMDB-47307, PDB-9dyk:
BEST2 + GABA closed state
Method: EM (single particle) / Resolution: 2.27 Å

47308

9dyl

EMDB-47308, PDB-9dyl:
BEST1 + PABA open state
Method: EM (single particle) / Resolution: 2.6 Å

47309

9dym

EMDB-47309, PDB-9dym:
BEST1 + PABA intermediate state
Method: EM (single particle) / Resolution: 2.67 Å

47310

9dyn

EMDB-47310, PDB-9dyn:
BEST2 + PABA open state
Method: EM (single particle) / Resolution: 2.44 Å

47311

9dyo

EMDB-47311, PDB-9dyo:
BEST2 + PABA closed state
Method: EM (single particle) / Resolution: 2.57 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-GLU:
GLUTAMIC ACID

ChemComp-CL:
Unknown entry

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID

ChemComp-PAB:
4-AMINOBENZOIC ACID

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / calcium-activated chloride channel / Glutamate-bound anion channel / channel-activator complex / GABA-bound anion channel / para-aminobenzoic acid (PABA)-bound anion channel

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