Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment
Abstract 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 a...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54938-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850048910348779520 |
|---|---|
| author | Aaron P. Owji Jingyun Dong Alec Kittredge Jiali Wang Yu Zhang Tingting Yang |
| author_facet | Aaron P. Owji Jingyun Dong Alec Kittredge Jiali Wang Yu Zhang Tingting Yang |
| author_sort | Aaron P. Owji |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-b5bf1810ca514d98bba32bc385eccbf7 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b5bf1810ca514d98bba32bc385eccbf72025-08-20T02:53:50ZengNature PortfolioNature Communications2041-17232024-12-0115111010.1038/s41467-024-54938-zNeurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatmentAaron P. Owji0Jingyun Dong1Alec Kittredge2Jiali Wang3Yu Zhang4Tingting Yang5Department of Ophthalmology, Columbia UniversityDepartment of Ophthalmology, Columbia UniversityDepartment of Ophthalmology, Columbia UniversityDepartment of Ophthalmology, Columbia UniversityDepartment of Ophthalmology, Columbia UniversityDepartment of Ophthalmology, Columbia UniversityAbstract 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.https://doi.org/10.1038/s41467-024-54938-z |
| spellingShingle | Aaron P. Owji Jingyun Dong Alec Kittredge Jiali Wang Yu Zhang Tingting Yang Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment Nature Communications |
| title | Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment |
| title_full | Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment |
| title_fullStr | Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment |
| title_full_unstemmed | Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment |
| title_short | Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment |
| title_sort | neurotransmitter bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment |
| url | https://doi.org/10.1038/s41467-024-54938-z |
| work_keys_str_mv | AT aaronpowji neurotransmitterboundbestrophinchannelstructuresrevealsmallmoleculedrugtargetingsitesfordiseasetreatment AT jingyundong neurotransmitterboundbestrophinchannelstructuresrevealsmallmoleculedrugtargetingsitesfordiseasetreatment AT aleckittredge neurotransmitterboundbestrophinchannelstructuresrevealsmallmoleculedrugtargetingsitesfordiseasetreatment AT jialiwang neurotransmitterboundbestrophinchannelstructuresrevealsmallmoleculedrugtargetingsitesfordiseasetreatment AT yuzhang neurotransmitterboundbestrophinchannelstructuresrevealsmallmoleculedrugtargetingsitesfordiseasetreatment AT tingtingyang neurotransmitterboundbestrophinchannelstructuresrevealsmallmoleculedrugtargetingsitesfordiseasetreatment |