Owji Aaron P, Dong Jingyun, Kittredge Alec, Wang Jiali, Zhang Yu, Yang Tingting
Department of Ophthalmology, Columbia University, New York, NY, USA.
Nat Commun. 2024 Dec 30;15(1):10766. doi: 10.1038/s41467-024-54938-z.
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.
Best1和Best2是阴离子通道Bestrophin家族的两个成员，分别在预防视网膜变性和维持眼内压方面发挥关键作用。在此，我们解析了结合谷氨酸和γ-氨基丁酸（GABA）的Best2结构，它们分别在Best2上描绘了一个细胞内谷氨酸结合位点和一个细胞外GABA结合位点，确定细胞外GABA是Best2的可渗透激活剂，并阐明了谷氨酸、GABA和谷氨酰胺合成酶在体内对Best2的共同调节作用。我们还进一步鉴定了多种小分子作为Bestrophin通道的激活剂。对一种强效激活剂4-氨基苯甲酸（PABA）进行了广泛分析：解析了结合PABA的Best1和Best2结构，其显示出与结合GABA的Best2相同的结合位点；PABA处理可挽救患者来源的Best1突变的功能缺陷。总之，我们的结果证明了多种小分子候选物作为治疗Bestrophin相关疾病/病症的临床适用药物的作用机制和潜力。
