Please be patient while the structures in the left frame load. In order to display all of the structures in the tour properly, press 'View' buttons below in order (from 1 to the end).
The leucine transporter (LeuT) belongs to a class of transmembrane proteins that use the electrochemical potential of specific ions to catalyze the transport of various organic substrates across the cell membrane. In eukaryotic organisms, these proteins play a very important role in neural signalling and their malfunction is believed to be a cause of many neural diseases.
This tour explores the structure and function of a bacterial leucine transporter isolated from Aquifex aeolicus (LeuTAa). LeuTAa utilizes the existing electrochemical potential of Na+ ions to facilitate the uptake of amino acid leucine. The intracellular concentration of Na+ is lower than the extracellular concentration of Na+. The concentration difference creates an electrochemical potential gradient that is used to catalyze the uptake of organic substrates (in this case leucine). The transport is not dependent on any other source of energy (for example, ATP). The LeuTAa reaction is:
2Na+out + leucineout → 2Na+in + leucinein 
The human homologue of LeuTAa is dependent on Cl- as well as Na+ concentration: they belong to a class of Na+/Cl- dependent transporters from the solute carrier 6 (SLC6) family (also referred to as neurotransmitter sodium symporters, or NSS). They transport many biologically important monoamines, for example dopamine (DA), noradrenaline and serotonin. The human SLC6 transporters are also primary targets for addictive substances (cocaine and amphetamine) as well as for drugs for the treatment of central nervous system disorders .
Aa transporter consists of two identical subunits (it is a homodimer), one subunit is coloured yellow, the other blue. (Unless otherwise noted, in each view the extracellular side of the transporter structure is always pointing upwards.)
Aa click on image thumbnail below.
Since the two subunits are identical, the remainder of the tour will concentrate only on one subunit.
Aa is composed of twelve transmembrane (TM) alpha helix segments (green and red). There are two very short β-sheets (blue) and numerous loops (yellow). The two red α helices, TM9 and TM12, are points of contact between the two subunits in the homodimer. This is a unique fold among membrane proteins but it is typical for the SLC6 family of Na+-dependent symporters. The monomer is about 70 Å tall and approximately 48 Å in diameter.
+ ions inside the protein.
+ ion. All donor atoms are oxygens. Five donor atoms are provided by the residues located on TM1 (Ala22 and Asn27) and TM6 (two oxygens from Thr254 and one from Asn286). The sixth coordination site is occupied by the oxygen atom from deprotonated carboxyl group on leucine.
+ ion. Again, all donor atoms are oxygen atoms. Five different residues provide the donor atoms: Glu20, Val23 (both on TM1), Ala351, Thr354 and Ser355 (all on TM8).
+-O distances for both Na sites.
The mechanism behind the selectivity for Na+ over K+ found in these proteins is not fully understood. For the Na1 site, the presence of negatively charged ligand (Leu) is considered important for selectivity because it can off-set relatively high dehydration energy for Na+ cation and would prefer a cation with higher charge-to-radius ratio. The 'snug-fit' provided by a chelating Thr254 further increases the preference for the smaller sodium cation. The low coordination number of the Na2 site and ligands located close in the protein primary structure (forming a small-size cavity) are two likely features that dictate the preference of this site for Na+ .
2 groups) and non-polar (isopropyl group) ends of the molecule. The polar end is stabilized through polar interactions (yellow lines indicate selected polar leucine-protein interactions). The most noteworthy interaction is between the carboxylate on leucine and Na+ at the Na1 site (left hand side of the display).
Aa transporter has two gates: one opens to the extracellular space the other to the intracellular space. Two pairs of amino acids, a pair for each gate, serve as the 'gate keepers': red pair (top) for the extracellular and blue pair (bottom) for the intracellular gate. In this structure, both gates are closed and it is said that the LeuTAa is in occluded-state.
open-to-out protein conformation) if leucine is replaced with the LeuTAa inhibitors. The display on the right shows the LeuTAa structure with one possible inhibitor - tryptophan (ball-and-stick model in the middle).
Aa. Feel free to explore it further.