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The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating.

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Title: The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating.
Authors: Gonzalez-Sanabria, Naileth1,2, Contreras, Gustavo F.1, Rojas, Maximiliano3, Duarte, Yorley3, Gonzalez-Nilo, Fernando D.3 fernando.gonzalez@unab.cl, Perozo, Eduardo1 eperozo@uchicago.edu, Latorre, Ramon2 ramon.latorre@uv.cl
Source: Proceedings of the National Academy of Sciences of the United States of America. 2/3/2026, Vol. 123 Issue 5, p1-9. 18p.
Subjects: Calcium-dependent potassium channels, Ligand binding (Biochemistry), Drug target, Electron microscopy, Molecular dynamics, Allosteric regulation
Abstract: BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore's open conformation remain unclear. Using cryoelectron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within a pocket formed by the S6/RCK1 linker and the S4 transmembrane segment. Our simulations suggest that agonist binding promotes a twisting motion in the S6 segment, enabling critical interactions with residues K330, K331, and F223. These findings provide a molecular model for the mechanism of NS1619 and suggest that its binding site can accommodate other agonists, highlighting a promising target for therapeutic development. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating.
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  Data: <searchLink fieldCode="DE" term="%22Calcium-dependent+potassium+channels%22">Calcium-dependent potassium channels</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand+binding+%28Biochemistry%29%22">Ligand binding (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+target%22">Drug target</searchLink><br /><searchLink fieldCode="DE" term="%22Electron+microscopy%22">Electron microscopy</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Allosteric+regulation%22">Allosteric regulation</searchLink>
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  Data: BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore's open conformation remain unclear. Using cryoelectron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within a pocket formed by the S6/RCK1 linker and the S4 transmembrane segment. Our simulations suggest that agonist binding promotes a twisting motion in the S6 segment, enabling critical interactions with residues K330, K331, and F223. These findings provide a molecular model for the mechanism of NS1619 and suggest that its binding site can accommodate other agonists, highlighting a promising target for therapeutic development. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2507707123
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        Text: English
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      – SubjectFull: Calcium-dependent potassium channels
        Type: general
      – SubjectFull: Ligand binding (Biochemistry)
        Type: general
      – SubjectFull: Drug target
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      – SubjectFull: Electron microscopy
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      – SubjectFull: Molecular dynamics
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      – SubjectFull: Allosteric regulation
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      – TitleFull: The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating.
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              Text: 2/3/2026
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              Y: 2026
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