Congratulations to Anshu Mittal and all of our co-authors!

Comparison of multiple SV2A complexes reveals that primary site occupancy shapes the conformation of the lumenal half of the transmembrane domain, influencing how UCB1244283 binds via a connected network that differentially stabilizes TM1 in either an open or closed conformation.

Structures of SV2A-UCB-J and SV2A-UCB7361 show that UCB1244283 binding is only possible when the primary site ligand does not overlap with the allosteric site, and that repositioning of residues in the allosteric site is critical for allosteric ligand binding.

The allosteric site, formed by hydrophobic and uncharged residues, is an uncharacterized small-molecule binding site in SV2A. Structural analysis and mutagenesis demonstrate that an allosteric network between the primary and allosteric sites governs high-affinity ASM binding.

The SV2A-BRV-UCB1244283 structure reveals how UCB1244283 allosterically enhances BRV binding by occupying an allosteric site near the primary binding site, preventing BRV dissociation.

Congratulations Anshu and Matt and all of our co-authors!

These differences are primarily localized to the luminal regions of the TMD, particularly in TM1 and TM8, which resulted in a locked TMD conformation in our structure.

Here we show that UCB1244283 occupies an allosteric site near the primary binding site, preventing ASM dissociation. Distinct conformational differences between the SV2A-BRV-UCB1244283 and other SV2A-ligand complexes, particularly in the transmembrane domain, influence binding at both sites.