Structure of the human K_2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site

Shatabdi Roy-Chowdhury¹, Seil Jang¹, Fayal Abderemane-Ali^{1

2}, Fiona Naughton¹, Michael Grabe^{1

3}, Daniel L Minor Jr^{4

5

6

7

8}

Affiliations

¹ Cardiovascular Research Institute, UCSF Medical Center, San Francisco, CA, USA.
² Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
⁴ Cardiovascular Research Institute, UCSF Medical Center, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁵ Departments of Biochemistry and Biophysics and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁶ California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁷ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁸ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. daniel.minor@ucsf.edu.

PMID: 40011746
DOI: 10.1038/s41594-024-01476-3

Structure of the human K_2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site

Shatabdi Roy-Chowdhury et al. Nat Struct Mol Biol. 2025 Jul.

. 2025 Jul;32(7):1154-1166.

doi: 10.1038/s41594-024-01476-3. Epub 2025 Feb 26.

Authors

Shatabdi Roy-Chowdhury¹, Seil Jang¹, Fayal Abderemane-Ali^{1

2}, Fiona Naughton¹, Michael Grabe^{1

3}, Daniel L Minor Jr^{4

5

6

7

8}

Affiliations

¹ Cardiovascular Research Institute, UCSF Medical Center, San Francisco, CA, USA.
² Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
⁴ Cardiovascular Research Institute, UCSF Medical Center, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁵ Departments of Biochemistry and Biophysics and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁶ California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁷ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁸ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. daniel.minor@ucsf.edu.

PMID: 40011746
DOI: 10.1038/s41594-024-01476-3

Erratum in

Author Correction: Structure of the human K_2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site.
Roy-Chowdhury S, Jang S, Abderemane-Ali F, Naughton F, Grabe M, Minor DL Jr. Roy-Chowdhury S, et al. Nat Struct Mol Biol. 2025 Jul;32(7):1318. doi: 10.1038/s41594-025-01553-1. Nat Struct Mol Biol. 2025. PMID: 40234720 No abstract available.

Abstract

Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K_2P13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly understood mechanisms. Here we present cryo-electron microscopy structures of human THIK1 and mutants, revealing a unique two-chamber aqueous inner cavity obstructed by a hydrophilic barrier important for gating, the flow restrictor, and a P1-M4 intersubunit interface lipid at a site, the PUFA site, corresponding to the K_2P small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, K_v7.1, reveals a shared modulatory role for the pore domain intersubunit interface, providing a framework for understanding PUFA action on the VGIC superfamily. Our findings reveal the distinct THIK1 architecture, highlight the importance of the P1-M4 interface for K_2P control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Update of

Structure of the human K_2P13.1(THIK-1) channel reveals a novel hydrophilic pore restriction and lipid cofactor site.
Roy-Chowdhury S, Jang S, Abderemane-Ali F, Naughton F, Grabe M, Minor DL Jr. Roy-Chowdhury S, et al. bioRxiv [Preprint]. 2024 Jun 27:2024.06.26.600491. doi: 10.1101/2024.06.26.600491. bioRxiv. 2024. Update in: Nat Struct Mol Biol. 2025 Jul;32(7):1154-1166. doi: 10.1038/s41594-024-01476-3. PMID: 38979306 Free PMC article. Updated. Preprint.

References

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Structure of the human K_2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site

Affiliations

Structure of the human K_2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources