Show Notes
️ Episode 246: SV2A structural pharmacology and allosteric occlusion
In this episode of PaperCast Base by Base, we explore High-resolution cryo-EM structures of human SV2A reveal that orthosteric ligands induce an occluded MFS conformation and a secondary allosteric pocket modulates ligand binding
Study Highlights:
The authors report sub-3 Å cryo-EM structures of human SV2A in the apo state and in complexes with levetiracetam, UCB-J, padsevonil, and the allosteric modulator UCB1244283. Levetiracetam and UCB-J bind the central cavity and drive inward movement of TM1 with Phe188 sealing the lumen, producing complete occlusion with levetiracetam and partial occlusion with UCB-J. UCB1244283 occupies a distinct allosteric site ~13 Å above the orthosteric pocket, reshapes the orthosteric site, lowers UCB-J Kd, increases Bmax, and slows ligand dissociation. Padsevonil binds both orthosteric and allosteric sites, precluding UCB1244283-mediated potentiation and illustrating overlapping but flexible allosteric interactions.
Conclusion:
SV2A uses orthosteric-induced occlusion combined with a secondary allosteric pocket to regulate ligand engagement, offering a structural blueprint for designing SV2A-specific modulators
Music:
Enjoy the music based on this article at the end of the episode.
Reference:
Pidathala S., Chen X., Dai Y., Gorgulla C., Niu Y., Liu F., Lee C.-H. Structural pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily. Nature Communications. 2025;16:10748. https://doi.org/10.1038/s41467-025-65781-1
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
Official website https://basebybase.com
Castos player https://basebybase.castos.com
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.castos.com/episodes/sv2a-allosteric-occlusion
Episode Slug: sv2a-allosteric-occlusion
Keywords: SV2A, allosteric modulation, cryo-EM, levetiracetam, padsevonil
