| TCID | Description | Domain | Kingdom/Phylum | Example |
|---|---|---|---|---|
| 2.A.22.1.7 | Dopamine transporter. The 3-d structure is known to 3.0 Å resolution (Penmatsa et al. 2013). The crystal structure, bound to the tricyclic antidepressant nortriptyline, shows the transporter locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. |
Eukaryota | Metazoa | Dopamine transporter of Drosophila melanogaster |
| 2.A.22.4.2 | The amino acid (leucine):2 Na+ symporter, LeuTAa (Yamashita et al., 2005). LeuT possesses two ion binding sites, NA1 and NA2, both highly specific for Na+ but with differing mechanisms of binding (Noskov and Roux, 2008). X-ray structures have been determined for LeuT in substrate-free outward-open and apo inward-open states (Krishnamurthy and Gouaux, 2012). Extracytoplasmic substrate binding at an allosteric site controls activity (Zhao et al. 2011). It has been proposed that the 5 TMS repeat derived from a DedA domain (9.B.27; Khafizov et al. 2010). Mechanistic aspect of Na+ binding have been studied (Perez and Ziegler 2013). Structural studies of mutant LeuT proteins suggest how antidepressants bind to biogenic amine transporters (Wang et al. 2013). The detailed mechanism was studied by Zhao and Noskov, 2013. Uptake involves movement of the substrate amino acid from the outward facing binding site, S1, to the inward facing binding site, S2, coupled with confrmational changes in the protein (Cheng and Bahar 2013). The complete substrate translocation pathway has been proposed (Cheng and Bahar 2014). The inward facing conformation of LeuT has been solved (Grouleff et al. 2015). Substrate-induced unlocking of the inner gatemay determinethe catalytic efficiency of the transporter (Billesbølle et al. 2015). Of the two Na+ binding sites, occupation of Na2 stabilizes outward-facing conformations presumably through a direct interaction between Na+ and transmembrane helices 1 and 8 whereas Na+ binding at Na1 influences conformational change through a network of intermediary interactions (Tavoulari et al. 2015). TMS1A movements revealed a substantially different inward-open conformation in lipid bilayer from that inferred from the crystal structure, especiallly with respect to the inner vestibule (Sohail et al. 2016). Partial unwinding of transmembrane helices 1, 5, 6 and7 drives LeuT from a substrate-bound, outward-facing occluded conformation toward an inward-facing open state (Merkle et al. 2018). A conserved tyrosine residue in the substrate binding site is required for substrate binding to convert LeuT to inward-open states by establishing an interaction between the two transporter domains (Zhang et al. 2018). The X-ray structure of LeuT in an inward-facing occluded conformation has revealed the mechanism of substrate release (Gotfryd et al. 2020). This involves a major tilting of the cytoplasmic end of TMS5, which, together with release of the N-terminus but without coupled movement of TM1) opens a wide cavity towards the second Na+ binding site. The X-ray structure of LeuT in an inward-facing occluded conformation has been solved, revealing the mechanism of substrate release (Gotfryd et al. 2020). | Bacteria | Aquificae | LeuTAa of Aquifex aeolicus (2A65_A) |
| 2.A.3.8.19 | B(0,+)-type amino acid transporter 1 (B(0,+)AT) (Glycoprotein-associated amino acid transporter b0,+AT1) (Solute carrier family 7 member 9). The cryo-EM structure of the human heteromeric amino acid transporter b(0,+)AT-rBAT complex has been solved (Yan et al. 2020). The two subunits, a heavy chain and a light chain are linked by a disulfide bridge. The light chain forms a heterodimer with rBAT, a heavy chain which mediates the membrane trafficking of b(0,+)AT. The b(0,+)AT-rBAT complex is an obligatory exchanger, which mediates the influx of cystine and cationic amino acids and the efflux of neutral amino acids in the kidney and small intestine. Yan et al. 2020 reported the cryo-EM structure of the human b(0,+)AT-rBAT complex alone and in complex with an arginine substrate at resolutions of 2.7 and 2.3 Å, respectively. The overall structure is a dimer of heterodimers. Arg is bound to the substrate binding site in an occluded pocket. The cryoEM structure reveals a heterotetrameric protein assembly composed of two heavy and two light chain subunits, respectively. The interaction between the two units is mediated by dimerization of the heavy chain subunits and does not include participation of the light chain subunits (Wu et al. 2020). The b((0,+))AT1 transporter adopts a LeuT fold and is in an inward-facing conformation. An amino-acid-binding pocket is formed by transmembrane helices 1, 6, and 10 and is conserved among SLC7 transporters. |
Eukaryota | Metazoa | SLC7A9 of Homo sapiens |
| 2.A.55.3.7 | H+-stimulated, divalent metal cation uptake system, MntH of 436 aas and 11 TMSs. The x-ray structure has been determined, revealing the probable ion translocation pathway (Bozzi et al. 2016). Metal ion and proton may enter the transporter via the same external pathway to the ir binding sites, but they follow separate routes to the cytoplasm, which could facilitate the co-transport of two cationic species (Bozzi et al. 2019). The results illustrate the flexibility of the LeuT fold to support a broad range of substrate transport and conformational change mechanisms. Transmembrane helix 6b links proton- and metal-release pathways and drives conformational changes (Bozzi et al. 2019). |
Bacteria | Deinococcus-Thermus | MntH of Deinococcus radiodurans |