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Structure paper

TitleStructure of the human K13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 7, Page 1154-1166, Year 2025
Publish dateFeb 26, 2025
AuthorsShatabdi Roy-Chowdhury / Seil Jang / Fayal Abderemane-Ali / Fiona Naughton / Michael Grabe / Daniel L Minor /
PubMed AbstractPolyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly ...Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K13.1 (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 small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, K7.1, 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 control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.
External linksNat Struct Mol Biol / PubMed:40011746
MethodsEM (single particle)
Resolution2.36 - 2.95 Å
Structure data

44870

9bsn

EMDB-44870, PDB-9bsn:
Structure of human K2P13.1 (THIK-1) in lipid nanodisc
Method: EM (single particle) / Resolution: 2.7 Å

44978

9bws

EMDB-44978, PDB-9bws:
Structure of human k2P13.1 (THIK-1) S136P Y273A in lipid nanodisc
Method: EM (single particle) / Resolution: 2.39 Å

45034

9byi

EMDB-45034, PDB-9byi:
Structure of human K2P13.1 (THIK1) in detergent
Method: EM (single particle) / Resolution: 2.95 Å

45075

9c07

EMDB-45075, PDB-9c07:
Structure of K2P13.1 (THIK1) S136P in detergent
Method: EM (single particle) / Resolution: 2.73 Å

45077

9c09

EMDB-45077, PDB-9c09:
Structure of K2P13.1 (THIK1) S136P in lipid nanodisc
Method: EM (single particle) / Resolution: 2.36 Å

Chemicals

ChemComp-D12:
DODECANE

ChemComp-D10:
DECANE

ChemComp-OCT:
N-OCTANE

ChemComp-EIC:
LINOLEIC ACID

ChemComp-K:
Unknown entry

ChemComp-HEX:
HEXANE

ChemComp-R16:
HEXADECANE

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Potassium channel / K2P / ion channel / k2p channel / membrane protein

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