RES binding site. TBZ (also called Nitoman and Xenazine), dihydrotetrabenazine (DTBZOH), ketanserin (KET), and the drug lobeline bind to the TBZ binding site. Amphetamine, methamphetamine and GZ-7931 are also known to interact with VMAT2.Vesicular monoamine transporter 2#Binding sites and ligands Inhibitor affinity varies among VMAT isoforms. RES and KET have higher inhibitory affinity for VMAT2–mediated 5HT transport than for that of VMAT1; TBZ seems to inhibit VMAT2 exclusively. The residues asp33 and ser180, 181, and 182 are believed to be involved in substrate recognition, and interact with the protonated amino group and hydroxyl group on the catechol or indole rings. Cocaine and methylphenidate (MPD, also known as Ritalin and Concerta) are believed to interact with VMAT2 to cause a shift in VMAT2 "from a plasmalemmal membrane-associated fraction to a vesicle-enriched, nonmembrane-associated fraction." RES binding site Consistent with catecholamine-binding affinity, RES has a threefold higher affinity for VMAT2 than for VMAT1. The RES binding site is known to be hydrophobic, which is thought to contribute to ligand binding affinity. Methamphetamine binds to the RES site on VMATs. The current working model proposes that RES and the substrate bind to a single site in a pH-gradient modulated conformational structure of the transporter. The conformation occurs after the transport of one H+ across the membrane and into the vesicle; proton transport drives the substrate recognition site from the lumen to the cytoplasmic surface of the vesicle for RES and substrate binding. Methoxytetrabenazine (MTBZ) may bind to the RES binding site, based on studies indicating that RES significantly inhibited MTBZ-binding. Amiodarone is also believed to inhibit monoamine vesicular uptake by binding to the RES binding site. TBZ binding site TBZ and dihydrotetrabenazine (DTBZOH) are believed to bind to a different binding site from the RES/substrate binding site, or to a different conformation of the RES/substrate binding site. This site is believed to be located at the N-terminus, based on studies done in bovine VMAT2. Tyr434 and asp461 are identified as being responsible for the high-affinity interaction of TBZ, serotonin, and histamine in VMAT2. Unlike methamphetamine, amphetamine binds to the TBZ site on hVMAT2. Unlike RES inhibition, TBZ inhibition is only affected by very high concentrations of monoamines; however, single injections of RES can inhibit TBZ binding. ketanserin (KET) and lobeline also bind to the TBZ binding site conformation. Glycosolation sites: N- and C-linked terminals Three to four glycosolation sites exist in the vesicular matrix