View source for 9dym


==BEST1 + PABA intermediate state==
<StructureSection load='9dym' size='340' side='right'caption='[[9dym]], [[Resolution|resolution]] 2.67&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dym]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DYM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DYM FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.67&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PAB:4-AMINOBENZOIC+ACID'>PAB</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9dym FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dym OCA], [https://pdbe.org/9dym PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dym RCSB], [https://www.ebi.ac.uk/pdbsum/9dym PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dym ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/BEST1_HUMAN BEST1_HUMAN] MRCS syndrome;Adult-onset foveomacular vitelliform dystrophy;Retinitis pigmentosa;Autosomal dominant vitreoretinochoroidopathy;Nanophthalmos;Best vitelliform macular dystrophy;Autosomal recessive bestrophinopathy. The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/BEST1_HUMAN BEST1_HUMAN] Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+) (PubMed:11904445, PubMed:12907679, PubMed:18179881, PubMed:18400985, PubMed:19853238, PubMed:21330666, PubMed:26200502, PubMed:26720466, PubMed:35789156). Allows the movement of chloride and hydrogencarbonate (PubMed:11904445, PubMed:12907679, PubMed:18179881, PubMed:18400985, PubMed:19853238, PubMed:21330666, PubMed:26200502, PubMed:26720466, PubMed:35789156). Found in a partially open conformation leading to significantly smaller chloride movement (PubMed:35789156). Upon F2R/PAR-1 activation, the sequestered calcium is released into the cytosol of astrocytes, leading to the (Ca2+)-dependent release of L-glutamate into the synaptic cleft that targets the neuronal postsynaptic GRIN2A/NMDAR receptor resulting in the synaptic plasticity regulation (By similarity). Upon activation of the norepinephrine-alpha-1 adrenergic receptor signaling pathway, transports as well D-serine than L-glutamate in a (Ca2+)-dependent manner, leading to activation of adjacent NMDAR receptors and therefore regulates the heterosynaptic long-term depression and metaplasticity during initial memory acquisition (By similarity). Releases the 4-aminobutanoate neurotransmitter in a (Ca2+)-dependent manner, and participates in its tonic release from cerebellar glial cells (By similarity).[UniProtKB:O88870]<ref>PMID:11904445</ref> <ref>PMID:12907679</ref> <ref>PMID:18179881</ref> <ref>PMID:18400985</ref> <ref>PMID:19853238</ref> <ref>PMID:21330666</ref> <ref>PMID:26200502</ref> <ref>PMID:26720466</ref> <ref>PMID:35789156</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 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<ref>PMID:39737942</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9dym" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kittredge A]]
[[Category: Owji AP]]
[[Category: Yang T]]
[[Category: Zhang Y]]