Fig. 4: Molecular dynamics (MD) simulations of lumen-facing VMAT2-5-HT structure under different protonation conditions.
From: Drug inhibition and substrate transport mechanisms of human VMAT2
a Estimated pKa values of acidic residues in the VMAT2-5HT without 5-HT. The cyan and pink bars represent the pKa values of the residues on the lumen and cytosol side, respectively. Dashed lines indicate cytoplasmic (cyan) and luminal (pink) pH values. b–f Root mean square deviation (RMSD) plots of MD simulations and corresponding MD snapshots of the 5-HT-bound lumen-facing VMAT2 structure, with only E312 protonated (b), only D399 protonated (c), both E312 and D399 protonated (d), both D399 and D426 protonated (e), or all E312, D399 and D426 protonated (f). g A summarized diagram depicting the change in substrate pose relative to the protonation site during substrate release. h Fluorescent substrate FFN206 uptake for wild-type VMAT2 and mutants. Data were normalized to VMAT2WT and are presented as mean ± SEM; n = 4 biological replicates. One-way ANOVA; **** P < 0.0001. Source data are provided as a Source Data file. i Schematic illustrating the transport and inhibition mechanisms during VMAT2 transport, using 5-HT as an example.
