8J75

Human high-affinity choline transporter CHT1 in the HC-3-bound outward-facing open conformation, monomeric state

Summary for 8J75

• Entry DOI: 10.2210/pdb8j75/pdb
• EMDB information: 36027
• Descriptor: High affinity choline transporter 1, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (2S,2'S)-2,2'-biphenyl-4,4'-diylbis(2-hydroxy-4,4-dimethylmorpholin-4-ium) (3 entities in total)
• Functional Keywords: cht1, slc5a7, high affinity choline transporter, choline transporter, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 64240.22

Authors

Gao, Y.,Qiu, Y.,Zhao, Y. (deposition date: 2023-04-27, release date: 2024-04-10, Last modification date: 2024-10-16)

Primary citation

Qiu, Y.,Gao, Y.,Huang, B.,Bai, Q.,Zhao, Y.
Transport mechanism of presynaptic high-affinity choline uptake by CHT1.
Nat.Struct.Mol.Biol., 31:701-709, 2024

PubMed Abstract: Choline is a vital nutrient and a precursor for the biosynthesis of essential metabolites, including acetylcholine (ACh), that play a central role in fetal development, especially in the brain. In cholinergic neurons, the high-affinity choline transporter (CHT1) provides an extraordinarily efficient reuptake mechanism to reutilize choline derived from intrasynaptical ACh hydrolysis and maintain ACh synthesis in the presynapse. Here, we determined structures of human CHT1 in three discrete states: the outward-facing state bound with the competitive inhibitor hemicholinium-3 (HC-3); the inward-facing occluded state bound with the substrate choline; and the inward-facing apo open state. Our structures and functional characterizations elucidate how the inhibitor and substrate are recognized. Moreover, our findings shed light on conformational changes when transitioning from an outward-facing to an inward-facing state and establish a framework for understanding the transport cycle, which relies on the stabilization of the outward-facing state by a short intracellular helix, IH1.

PubMed: 38589607
DOI: 10.1038/s41594-024-01259-w

Experimental method

ELECTRON MICROSCOPY (3.6 Å)