9D7X

The spm-bound structure

Summary for 9D7X

• Entry DOI: 10.2210/pdb9d7x/pdb
• EMDB information: 46619
• Descriptor: Green fluorescence protein,MFS-type transporter SLC18B1,membrane protein with spm, SPERMINE (3 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 82322.11

Authors

Lu, M.,Liu, B. (deposition date: 2024-08-17, release date: 2025-06-25)

Primary citation

Guo, Y.,Yang, G.,Liu, H.,Chai, J.,Chen, J.,Shanklin, J.,Liu, Q.,Liu, B.,Lu, M.
Structure and mechanism of human vesicular polyamine transporter.
Nat Commun, 16:4142-4142, 2025

PubMed Abstract: Polyamines play essential roles in gene expression and modulate neuronal transmission in mammals. Vesicular polyamine transporters (VPAT) from the SLC18 family exploit the transmembrane H gradient to translocate polyamines into secretory vesicles, enabling the quantal release of polyamine neuromodulators and underpinning learning and memory formation. Here, we report the cryo-electron microscopy structures of human VPAT in complex with spermine, spermidine, H, or tetrabenazine, elucidating discrete lumen-facing states of the antiporter and pivotal interactions between VPAT and its substrate or inhibitor. Leveraging structure-inspired mutagenesis studies and protein structure prediction, we deduce an unforeseen mechanism whereby the polyamine and H compete for multiple acidic protein residues both directly and indirectly, and rationalize how the antidopaminergic therapeutic tetrabenazine impedes vesicular transport of polyamines. This study unravels the mechanism of an H-coupled polyamine antiporter, reveals mechanistic diversity between VPAT and other SLC18 antiporters, and raises new prospects for combating human disorders of polyamine homeostasis.

PubMed: 40319071
DOI: 10.1038/s41467-025-59549-w

Experimental method

ELECTRON MICROSCOPY (3.4 Å)