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Structure paper

TitleStructural mechanisms of human sodium-coupled high-affinity choline transporter CHT1.
Journal, issue, pagesCell Discov, Vol. 10, Issue 1, Page 116, Year 2024
Publish dateNov 26, 2024
AuthorsJing Xue / Hongwen Chen / Yong Wang / Youxing Jiang /
PubMed AbstractMammalian sodium-coupled high-affinity choline transporter CHT1 uptakes choline in cholinergic neurons for acetylcholine synthesis and plays a critical role in cholinergic neurotransmission. Here, we ...Mammalian sodium-coupled high-affinity choline transporter CHT1 uptakes choline in cholinergic neurons for acetylcholine synthesis and plays a critical role in cholinergic neurotransmission. Here, we present the high-resolution cryo-EM structures of human CHT1 in apo, substrate- and ion-bound, hemicholinium-3-inhibited, and ML352-inhibited states. These structures represent three distinct conformational states, elucidating the structural basis of the CHT1-mediated choline uptake mechanism. Three ion-binding sites, two for Na and one for Cl, are unambiguously defined in the structures, demonstrating that both ions are indispensable cofactors for high-affinity choline-binding and are likely transported together with the substrate in a 2:1:1 stoichiometry. The two inhibitor-bound CHT1 structures reveal two distinct inhibitory mechanisms and provide a potential structural platform for designing therapeutic drugs to manipulate cholinergic neuron activity. Combined with the functional analysis, this study provides a comprehensive view of the structural mechanisms underlying substrate specificity, substrate/ion co-transport, and drug inhibition of a physiologically important symporter.
External linksCell Discov / PubMed:39587078 / PubMed Central
MethodsEM (single particle)
Resolution2.35 - 3.67 Å
Structure data

44497

9bfi

EMDB-44497, PDB-9bfi:
Cryo-EM structure of human CHT1 in the apo inward-open state
Method: EM (single particle) / Resolution: 2.66 Å

44498

9bfj

EMDB-44498, PDB-9bfj:
Cryo-EM structure of human CHT1 in the choline bound state
Method: EM (single particle) / Resolution: 2.35 Å

44499

9bfk

EMDB-44499, PDB-9bfk:
Cryo-EM structure of human CHT1 in the ML352 bound state
Method: EM (single particle) / Resolution: 2.85 Å

44593

9bim

EMDB-44593, PDB-9bim:
Cryo-EM structure of human CHT1 in the HC-3 bound outward-facing state
Method: EM (single particle) / Resolution: 3.67 Å

Chemicals

ChemComp-CHT:
CHOLINE ION

ChemComp-CL:
Unknown entry

ChemComp-NA:
Unknown entry

PDB-1aow:
ANNEXIN IV

ChemComp-HC6:
(2S,2'S)-2,2'-biphenyl-4,4'-diylbis(2-hydroxy-4,4-dimethylmorpholin-4-ium)

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Choline transporter

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