Neuronal signaling by monoaminergic neurotransmitters controls all aspects of human autonomic functions and behavior, and dysregulation of this leads to many neuropsychiatric diseases. Nearly 60 years ago (Carlsson et al., 1957; Kirshner, 1962 ), secretory vesicles prepared from adrenal glands were shown to contain an activity that accumulated epinephrine, norepinephrine, and serotonin in an ATP-dependent manner (Eiden and Weihe, 2011). Extensive characterization by many different laboratories of synaptic vesicles (SVs) in neurons showed that monoamine transport activity was also dependent on the proton gradient generated by the V-ATPase, exchanging two protons for one cationic monoamine (Henry et al., 1998; Eiden, 2000; Johnson, 1988; Eiden et al., 2004; Schuldiner et al., 1995). Monoamine transport was shown to be inhibited by non-competitive inhibitors such as tetrabenazine (TBZ) (Peter et al., 1994) and competitive inhibitors like reserpine which has been used to treat hypertension (Eiden and Weihe, 2011). Amphetamines were shown to be monoamine transporter substrates, eventually leading to vesicle deacidification, disruption of dopamine (DA) packaging in the SV, and DA release into the synapse (Freyberg et al., 2016). Cloning of the vesicular monoamine transporter (VMAT) in the 1990s (Liu et al., 1992; Peter et al., 1995; Erickson et al., 1992) revealed two different genes, VMAT1 and VMAT2, that were expressed in the adrenal medulla and brain, respectively (Peter et al., 1995; Weihe et al., 1994). VMAT2 is expressed in all monoaminergic neurons in the brain, including those for serotonin, norepinephrine, DA, epinephrine, and histamine (Eiden and Weihe, 2011), and is essential for loading these neurotransmitters into SVs. VMAT2 is fundamentally required for neurotransmitter recycling and release (Wang et al., 1997; Takahashi et al., 1997; Fon et al., 1997) and changes in VMAT1 and VMAT2 activities either through small-molecule agents or mutations are thought to contribute to many human neuropsychiatric disorders including infantile-onset Parkinson’s, schizophrenia, alcoholism, autism, and bipolar depression (Lohoff et al., 2006; Vaht et al., 2016; Fehr et al., 2013; Bohnen et al., 2006; Han et al., 2020; Simons et al., 2013; Lohoff et al., 2008).

VMAT1 and -2 are members of the solute carrier 18 (SLC18) family and are also known as SLC18A1 and SLC18A2. The SLC18 subfamily also includes the vesicular transporters for acetylcholine (Arvidsson et al., 1997) (VAChT, SLC18A3) and polyamines (Hiasa et al., 2014) (VPAT, SLC18B1). Sequence alignments also show that SLC18 transporters belong to the major facilitator superfamily (MFS) of membrane transport proteins which use an alternating access mechanism (Jardetzky, 1966; Mitchell, 1957) to transport substrate across membranes. SLC18 members are predicted to be comprised of 12 transmembrane (TM) spanning helices (TM1–12), which are arranged in two pseudosymmetric halves each with six TM helices containing a primary binding site for neurotransmitters, polyamines, and inhibitors located approximately halfway across the membrane (Radestock and Forrest, 2011; Figure 1a). Conformational changes driven by the proton electrochemical gradient are thought to alternatively expose the binding site to either side of the membrane allowing for transport of neurotransmitter from the cytoplasm to the lumen of SVs (Yaffe et al., 2013; Yaffe et al., 2016).

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VMAT2 and VMAT1 share 62% sequence identity but have distinct substrate specificity and pharmacological properties (Erickson et al., 1996). Small-molecule ligands such as TBZ and reserpine are high-affinity inhibitors of VMAT2, which prevent neurotransmitters from binding, arrest VMAT2 from cycling, and consequently reduce neuronal signaling. VMAT2 exhibits higher affinity for TBZ, monoamines, and amphetamines, whereas reserpine binds equally to both VMAT2 and VMAT1 (Peter et al., 1994). TBZ is the only drug which is approved for treatment of chorea associated with Huntington’s disease and has shown to be effective in various other hyperkinetic conditions such as tardive dyskinesia, dystonia, tics, and Tourette’s syndrome (Kaur et al., 2016). A proposed mechanism for TBZ inhibition of VMAT2 involves two sequential steps, initial low-affinity binding of TBZ to the lumenal-open state of VMAT2 which produces a conformational change, resulting in a high-affinity dead-end TBZ-bound occluded complex (; Scherman et al., 1983; Scherman and Henry, 1984; Ugolev et al., 2013).

Here, we report a structure of VMAT2 bound to TBZ at 3.1 Å resolution in an occluded conformation using single-particle cryo-electron microscopy (cryo-EM), describing the architecture of VMAT2, identifying the high-affinity TBZ binding site, and revealing the mechanisms of drug and neurotransmitter binding, inhibition, and transport.

The VMAT2-TBZ complex captures the transporter in a fully occluded state with the ligand binding site centrally located between the two repeated substructures TM1–6 and TM7–12. VMAT2 functions by alternating access which involves alternate exposure of the primary binding site to either side of the membrane and isomerization between a cytosolic-open and lumenal-open state in a mechanism known as the rocker-switch (Figure 6a and b; Eiden and Weihe, 2011; Radestock and Forrest, 2011; Drew et al., 2021). Studies have proposed that TBZ first enters VMAT2 from the lumenal side, binding to a lumenal-open conformation (Scherman et al., 1983). TBZ makes extensive contact with residues in the primary site, likely in a lower affinity state as the transporter subsequently closes to forming the high-affinity occluded state. The lumenal gates lock the transporter into an occluded state, preventing displacement by other ligands and producing a so-called dead-end complex (Yaffe et al., 2016; Kaur et al., 2016; Scherman et al., 1983; Chen et al., 2012; Figure 6a).

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Comparison of the TMD with more distantly related MFS transporters in other conformational states such as the outward-open VGLUT2 (Li et al., 2020) and inward-open GLUT4 (Yuan et al., 2022) models (1.2 Å RMSD) shows that the conformational changes involving TM1, -7, -8, and -11 are likely involved in mediating the transport cycle and alternating access (Figure 6—figure supplement 1). Comparison with the AlphaFold model shows that while the TMD is largely similar (1.1 Å RMSD overall difference in TMD), AlphaFold lacks several key features such as the conformations of the LLs and is unable to predict key details that are critical to ligand binding. Hence, computational docking could not identify the TBZ binding site using the AlphaFold-predicted model, alluding to the critical importance of our experimental structural data (and simulations based on that structure) for gaining insights into VMAT2 functional mechanisms.

To enable us to solve the structure of VMAT2, we developed an intrinsic fiducial tool consisting of mVenus and the anti-GFP Nb which provides a feature on the cytosolic side of the transporter. GFP and the GFP-Nb are ubiquitous tools used for cell biology, protein biochemistry, and structural biology and here we describe another application of this powerful toolkit. In contrast to traditional antibody-based campaigns which may require multiple rounds of screening and take many months or years to discover a suitable binder, our strategy only required us to make between 15 and 20 constructs to find a suitable chimera (Figure 1—figure supplement 1a–c). There are now many other similar methods such as the fusion of the target protein with BRIL and binding of the anti-BRIL Fab (Mukherjee et al., 2020) and fusions of maltose-binding protein and DARPin (Chen et al., 2023). However, since our strategy directly incorporates fluorescent proteins, this enables FSEC-based screening of constructs and monitoring fluorescence throughout purification (Hattori et al., 2012). One obvious disadvantage of all intrinsic fiducial strategies is that the fusion may distort the protein structure, but monitoring the functional activity and comparison with the wild-type protein should mitigate these problems.

Among human mutations in VMAT2 causing an infantile-onset form of parkinsonism (Jacobsen et al., 2016; Rilstone et al., 2013; Padmakumar et al., 2019), three mutants, P316A, P237H, and P387L, have been shown to extinguish monoamine transport. We find these residues are in LL4 and the lumenal ends of TM5 and -9, respectively (Figure 6—figure supplement 2). LL4 is involved in lumenal gating and the P316A variant would likely disrupt the conformation of the loop. In the case of P237H, a histidine would result in not only an insertion of a positively charged residue into the lumenal membrane interface but also in a reduction of the helical bend and would distort the connection of TM5 with TM6. The P387L variant would also disrupt helical connections and the overall architecture of the helix by insertion of a bulky residue into a small hydrophobic cavity. Therefore, we speculate that these SNPs alter the transporter’s ability to sample multiple conformations by suppressing transporter dynamics and perturbing VMAT2 stability and folding. Recently, many additional disease variants have been discovered (Saida et al., 2023), many of which are also found in the lumenal or cytoplasmic ends of TM helices, LL1, and the N- and C-termini, and our structure will provide insight into the functional and structural consequences of these variants.

Large aromatic side chains of the lumenal gating residues compartmentalize the transporter, likely ensuring directional transport of substrate. MD simulations revealed little variation in the pose of the aromatic gating residues comprising the inner gates (Figure 4—figure supplement 2d). It is interesting to note that substitution of Y433 with alanine resulted in enhanced transport while reducing DTBZ binding. Reduced inhibitor binding is likely due to disruption of π-stacking interactions, but the mechanism for enhanced transport remains unclear. The lumenal gates showed more movement in MD simulations of DA, likely owing to its residue composition and lack of strong interactions (Figure 5). Despite this observation, we assert that the tight hydrophobic environment prevents exchange into the lumenal space. These mechanisms of gating are atypical of MFS transporters which more commonly use salt bridges to gate access to the substrate binding site (Drew et al., 2021).

Of particular interest among gating residues is W318, which acts as a central plug to prevent solvent access to the transporter. Our mutagenesis analysis suggests that while a large residue is required for maintaining some transporter function, lack of charge also appears to be essential for inhibitor binding. Replacement of W318 with residues present in VMAT2 from other species, except for the phenylalanine mutant, failed to recapitulate any DTBZ binding. Interestingly, of these substitutions, only an arginine was able to fully recapitulate native transport, suggesting lumenal gating activity requires either a large, charged or a large aromatic residue. Our studies also suggest that E127 plays a role in lumenal gating by interacting with LL4 as substitution to alanine-reduced transport, and we speculate that large, charged groups at position 318 directly interact with E127 to maintain full transporter function. In contrast, DBTZ binding remained unaffected for the E127A mutant, suggesting a role for this residue in a later step of transporter closure of the lumenal compartment. Positively charged residues at position 318 may stabilize the lumenal gate and promote conformational cycling through enhanced interactions with negatively charged residues such as E127 but may prevent TBZ from entering the lumenal pathway of the transporter in any capacity. Conservation of this residue in the SLC18 family suggests that this is a common mechanism for lumenal gating. It is unclear what other structural adaptations are present to enable W318 replacement with large positively charged residues in other VMAT2 sequences, but we suspect that the overall architecture of the lumenal domain remains similar. We also note that the disulfide bond between LL1 and -4 plays a critical role in transport (Yao and Hersh, 2007), and the disulfide bond may function to restrict the dynamics of this region to allow W318 to occlude the neurotransmitter binding site during transport.

Residues R189 and K138 stand out as critical for drug binding and inhibition and substrate transport. Simulations highlight the role K138 may play in coordinating with the hydroxy group of neurotransmitters and enabling binding at the central site. These results are consistent with previously observed results demonstrating the critical role K138 plays in substrate transport (Yaffe et al., 2013; Merickel et al., 1997). Remarkably, even mutation to lysine at position 189 abolishes DTBZ binding while still retaining a small amount of transport activity, highlighting the specificity of the DTBZ binding site.

Our structure also provides important clues for understanding the chemical specificity and selectivity of TBZ binding, suggesting that the enhanced affinity of DTBZ is due to preferential interaction with N34. DTBZ is a metabolite of TBZ (Chen et al., 2012) which differs by only a hydroxyl group vs. a double bonded oxygen and binds to VMAT2 with approximately twofold higher affinity (Saida et al., 2023; Yao et al., 2011; Figure 4a). Our structure suggests that the amide of N34 acts as a hydrogen bond donor for TBZ, and in the case of DTBZ the hydroxyl of the ligand may act as a hydrogen bond donor for the carbonyl oxygen of N34. We hypothesize that this interaction is more favorable for DTBZ, leading to a higher binding affinity. Valbenazine, a TBZ analogue with a valine attached to the oxygen of the hydroxyl group of DTBZ, binds VMAT2 with a K_d of 150 nM (Ugolev et al., 2013; Uhlyar and Rey, 2018). We hypothesize that N34 does not form a favorable hydrogen bond with the oxygen of valbenazine and that addition of this larger moiety causes steric clashes in the binding site. Mutation of N34 nearly eliminated DTBZ binding, highlighting its importance in coordinating inhibitor binding. We found N34 is also important for transport, but its precise role remains unclear. Strikingly, replacement with glutamine had no effect on transport whereas aspartate had only a small effect. This suggests that N34 is likely involved in substrate coordination but may not be entirely essential. This is confirmed with the N34A substitution which still showed significant transport activity. In contrast, a threonine substitution was greatly detrimental, but we believe this is likely due to larger active site perturbations.

Comparison of the residues involved in TBZ binding in VMAT2 vs. VMAT1 also provides insight into the selectivity of TBZ by demonstrating that key differences in the ligand binding site are likely responsible for the reduction in TBZ binding affinity observed in VMAT1 (Peter et al., 1994). L37 and V232 are highlighted, and mutation to the equivalent residue in VMAT1, phenylalanine, and leucine, respectively, eliminated DTBZ binding but only reduced substrate transport. Given these results, we suggest these are the primary residues involved in determining TBZ selectivity for VMAT2 vs. VMAT1. We suspect VMAT1 exhibits structural differences compared with VMAT2 to accommodate the larger residues and maintain functional activity.

Through MD simulations, we gained insights into the effects of the protonation states of TBZ and E312. Protonation of TBZ at the amine resulted in an unstable complex, and a structure markedly different from the state resolved with electron microscopy. This suggests TBZ remains unprotonated when bound to the occluded state, as the protonated form will not remain in complex with VMAT2. We believe there may be other TBZ-bound states such as the lumenal-open state where TBZ may be protonated. However, in the terminal complex, E312 must remain protonated suggesting that E312 acts as a hydrogen bond donor to stabilize TBZ in the binding site. Our binding and transport studies further confirm this as the mutation of E312 to glutamine greatly reduces serotonin transport and DTBZ binding (Figure 4f and g). Moreover, mutation of E312 to an alanine has long been known to completely negate all TBZ binding and transport activities (Yaffe et al., 2013; Støve et al., 2022) again highlighting the requirement of hydrogen bond pairing with TBZ.

We also highlight three key polar networks which may be involved in conformational changes induced by proton binding during the transport cycle and are likely also involved in mediating proton transduction (Figure 6a). Taken together, we believe these networks play a critical role in mediating the conformation changes taking place in the transporter upon substrate or inhibitor binding. We hypothesize that the protonation of D33, E312, D399, and D426 would significantly perturb these interactions by breaking crucial hydrogen bond pairs and/or salt bridges, leading to opening of the cytosolic gate. This falls in line with previous work highlighting the role these residues play in transport through a variety of mutagenesis and functional experiments (Merickel et al., 1997; Støve et al., 2022). Given the known transport stoichiometry of two protons per neurotransmitter, we speculate that two protons may dissociate back into the lumen, perhaps driven by the formation of salt bridges between D33 and K138 or R189 and E312 for example in an cytosol-facing state. The asymmetry between these two networks is also striking, with the first network consisting of TM1, -4, and -11 being substantially larger. This may allow for larger conformational changes on this side and an overall asymmetry in the cytosolic-open state of the transporter. To our knowledge, this is also an atypical feature in MFS proteins (Drew et al., 2021) and would represent an interesting adaptation upon the rocker-switch mechanism.

Our studies lead us to propose a mechanism by which TBZ inhibits VMAT2 by first entering the transporter from the lumenal-open state and subsequently trapping it in an occluded state through a two-step mechanism centered around W318, which acts as a central plug to close off the lumenal compartment. This provides a basis for non-competitive inhibition as endogenous neurotransmitter is unable to compete for binding from the closed off cytosolic compartment (Figure 6a). Our results also provide insight into transporter function, and we propose a mechanism for substrate release from the central binding site (Figure 6b). The bound substrate coordinates in the binding site predominantly through interactions with E312 and K138. R189 is directed toward the lumenal space where it engages with one of two water channels. Water enters through these channels into the transporter, passing F135 and F334 and inducing conformational change. In our simulations, we find intrusion of water to cause W318 to flip out of the central site which enables neurotransmitter to dissociate from the transporter (Figure 6b).

In summary, we have developed a new fiducial tool incorporating mVenus and the GFP-Nb into the primary sequence of a previously intractable transport protein of great importance to human health. Cryo-EM of VMAT2 allowed us to pinpoint the lumenal and cytoplasmic gates, polar networks likely involved in conformational change and proton transduction, and the conformation and binding site of inhibitors. Our structure facilitated the discovery and detailed analysis of many residues involved in these key molecular mechanisms and enabled further extension in our understanding of neurotransmitter transport. Thus, by capturing the VMAT2 bound with TBZ along with subsequent mutagenesis, binding, transport, and computational experiments, our work delivers insights into the transporter’s mechanism of function and provides a framework for understanding the structural underpinnings of neurotransmitter release, transport, and inhibition in VMAT2 and other related transport proteins in the MFS family.

The coordinates and associated volumes for the cryo-EM reconstruction of the VMAT2-TBZ data set have been deposited in the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) under the accession codes 8THR and 41269.

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Author details

1. Michael P Dalton

   Department of Structural Biology, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Data curation, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5296-5099

2. Mary Hongying Cheng

   Laufer Center for Physical and Quantitative Biology, and Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States

   Contribution

   Data curation, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5833-8221

3. Ivet Bahar

   Laufer Center for Physical and Quantitative Biology, and Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United States

   Contribution

   Supervision, Funding acquisition, Methodology, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

4. Jonathan A Coleman

   Department of Structural Biology, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   coleman1@pitt.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0001-6195

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