Extended Data Fig. 7: Substrate and inhibitor binding.
From: Structural insights into vesicular monoamine storage and drug interactions
a-b, Structural superimposition of VMAT1 in unbound form and with bound dopamine showing the overall structures (a) and the substrate-binding pocket (b). c-e, Left, surface representation of the wrist-and-fist binding pocket with bound noradrenaline (c), serotonin (d), and histamine (e). Right, comparison of the binding of these monoamines (orange) with dopamine (dark grey). f, Mutations at the substrate-binding pocket reduces the binding affinity of FFN206. The binding of VMAT1 mutants is assessed by the fluorescence polarization of FFN206. Because most mutants do not achieve saturation in FFN206 binding even at very high protein concentration (100 µM), their relative affinities are estimated through binding potential (Bmax/Kd). Data are shown as mean ± s.e.m. from n = 3 biological replicates. g-h, Left, Amphetamine and MPP+ in the substrate binding pocket (surface representation). Right, comparison of their binding (orange) with dopamine (dark grey). i, Reserpine occupies the monoamine binding pocket. Left, the dopamine (dark grey) bound structure is superimposed onto the reserpine (orange) bound structure by the CTD. The protein sidechains illustrated are from the fixed reserpine-bound structure. Right, a 90-degree rotated view with the binding pocket (from the fixed reserpine-bound structure) shown in surface representation.
