View source for 9jo3


==Cryo-EM structure of human BKca channel-compound 10b complex==
<StructureSection load='9jo3' size='340' side='right'caption='[[9jo3]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9jo3]] is a 4 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=9JO3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9JO3 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]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L4E:5-azanyl-2-[2,3,5,6-tetrakis(fluoranyl)-4-(trifluoromethyl)phenoxy]phenol'>A1L4E</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=9jo3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9jo3 OCA], [https://pdbe.org/9jo3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9jo3 RCSB], [https://www.ebi.ac.uk/pdbsum/9jo3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9jo3 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KCMA1_HUMAN KCMA1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The BK(Ca) channel, a large-conductance calcium-activated potassium channel, plays a crucial role in maintaining the homeostasis of the micturition cycle and airway-related functions. In this study, we optimized a novel BK(Ca) channel activator, 4d, with a diphenyl ether structure identified from library screening. This led to the discovery of potent activators, 10b (EC(50) = 0.12 muM, cell-based assay) and 51b, an orally bioavailable derivative. Compound 10b demonstrated potent in vivo efficacy in a spontaneous hypertensive rat (SHR) of urinary incontinence model, while compound 51b showed dose-dependent cough suppression efficacy with an ED(50) of 11.8 mg/kg in a citric acid-induced cough model. Furthermore, we reported the cryo-electron microscopy (cryo-EM) structures of the BK(Ca) channel in complex with 10b and 51b at resolutions of 2.8 and 3.4 A. Based on structural analyses, we determined the binding sites and key interaction residues of 51b, which were validated via mutation studies.

Discovery of Diphenyl Ether Derivatives as Novel BK(Ca) Channel Activators: Structure-Activity Relationship, Cryo-EM Complex Structures, and In Vivo Animal Studies.,Park SB, Lee NY, Lee EY, Kim S, Lee N, Roh EC, Kim YG, Kim HJ, Jin MS, Park CS, Kim YC J Med Chem. 2025 Feb 13. doi: 10.1021/acs.jmedchem.4c02008. PMID:39947888<ref>PMID:39947888</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9jo3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jin MS]]
[[Category: Kim HJ]]
[[Category: Kim S]]
[[Category: Kim YC]]
[[Category: Kim YG]]
[[Category: Lee EY]]
[[Category: Lee N]]
[[Category: Lee NY]]
[[Category: Park CS]]
[[Category: Park S]]
[[Category: Roh EC]]