8Z3S
Activation mechanism and novel binding site of the BKCa channel activator CTIBD
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Summary for 8Z3S
| Entry DOI | 10.2210/pdb8z3s/pdb |
| EMDB information | 39753 |
| Descriptor | Calcium-activated potassium channel subunit alpha-1, 4-[4-(4-chlorophenyl)-3-(trifluoromethyl)-1,2-oxazol-5-yl]benzene-1,3-diol, CHOLESTEROL HEMISUCCINATE, ... (5 entities in total) |
| Functional Keywords | bkca channel, slo1, ctibd, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 507376.16 |
| Authors | |
| Primary citation | Lee, N.,Kim, S.,Lee, N.Y.,Jo, H.,Jeong, P.,Pagire, H.S.,Pagire, S.H.,Ahn, J.H.,Jin, M.S.,Park, C.S. Activation mechanism and novel binding sites of the BK Ca channel activator CTIBD. Life Sci Alliance, 7:-, 2024 Cited by PubMed Abstract: The large-conductance calcium-activated potassium (BK) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BK channel activator, altering and This study investigates CTIBD's activation mechanism, revealing its independence from the Ca and membrane voltage sensing of the BK channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BK-related pathophysiological conditions. PubMed: 39089879DOI: 10.26508/lsa.202402621 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.9 Å) |
Structure validation
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