9dyn | pdb_00009dyn
BEST2 + PABA open state
Structural highlights
FunctionBEST2_HUMAN Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+) (PubMed:11904445, PubMed:18400985, PubMed:32251414, PubMed:35789156, PubMed:36289327). Transports a large specter of anions, namely mediates the movement of chloride, L-glutamate and iodide (PubMed:11904445, PubMed:18400985, PubMed:32251414, PubMed:35789156, PubMed:36289327). Calcium-binding triggers the dilation of the aperture, but calcium-dependent gating is only effective when the size of the passing anion is bigger than the closed aperture (By similarity). Mediates the calcium-activated hydrogencarbonate movement and participates in colonic hydrogencarbonate secretion concomitant with mucin secretion (By similarity). In non-pigmented epithelium (NPE), mediates the efflux of intracellular L-glutamate; binding of intracellular L-glutamate activates and open both the neck and the aperture of the channel, leading to L-glutamate exit promoting chloride influx movement from the extracellular side in trans (PubMed:36289327). Also exhibits a directional permeability for intracellular glutamine, in a similar manner as for L-glutamate (PubMed:36289327).[UniProtKB:E1BF86][UniProtKB:Q8BGM5][1] [2] [3] [4] [5] Publication Abstract from PubMedBest1 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 gamma-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. Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment.,Owji AP, Dong J, Kittredge A, Wang J, Zhang Y, Yang T Nat Commun. 2024 Dec 30;15(1):10766. doi: 10.1038/s41467-024-54938-z. PMID:39737942[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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