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Structure paper

TitleStructure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3821, Year 2023
Publish dateJun 28, 2023
AuthorsJohanna L Syrjänen / Max Epstein / Ricardo Gómez / Hiro Furukawa /
PubMed AbstractCalcium homeostasis modulator 1 (CALHM1) is a voltage-dependent channel involved in neuromodulation and gustatory signaling. Despite recent progress in the structural biology of CALHM1, insights into ...Calcium homeostasis modulator 1 (CALHM1) is a voltage-dependent channel involved in neuromodulation and gustatory signaling. Despite recent progress in the structural biology of CALHM1, insights into functional regulation, pore architecture, and channel blockade remain limited. Here we present the cryo-EM structure of human CALHM1, revealing an octameric assembly pattern similar to the non-mammalian CALHM1s and the lipid-binding pocket conserved across species. We demonstrate by MD simulations that this pocket preferentially binds a phospholipid over cholesterol to stabilize its structure and regulate the channel activities. Finally, we show that residues in the amino-terminal helix form the channel pore that ruthenium red binds and blocks.
External linksNat Commun / PubMed:37380652 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 4.73 Å
Structure data

40229

8gmp

EMDB-40229, PDB-8gmp:
Cryo-EM structure of octameric human CALHM1 with a I109W point mutation
Method: EM (single particle) / Resolution: 2.8 Å

40230

8gmq

EMDB-40230, PDB-8gmq:
Chicken CALHM1 purified from mammalian cells
Method: EM (single particle) / Resolution: 3.36 Å

40231

8gmr

EMDB-40231, PDB-8gmr:
Cryo-EM structure of octameric human CALHM1
Method: EM (single particle) / Resolution: 3.76 Å

40232

8s8z

EMDB-40232, PDB-8s8z:
Cryo-EM structure of octameric human CALHM1 (I109W) in complex with ruthenium red
Method: EM (single particle) / Resolution: 3.91 Å

40233

8s90

EMDB-40233, PDB-8s90:
Cryo-EM structure of octameric human CALHM1 (I109W) in complex with ruthenium red (C1)
Method: EM (single particle) / Resolution: 4.73 Å

Chemicals

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-R2R:
ruthenium(6+) azanide pentaamino(oxido)ruthenium (1/4/2)

Source
  • homo sapiens (human)
  • gallus gallus (chicken)
KeywordsMEMBRANE PROTEIN / taste / assembly / calcium homeostasis modulator protein / channel / lipid binding / large-pore channel / ruthenium red

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