Coordination of Na(+) by monoamine ligands in dopamine, norepinephrine, and serotonin transporters.
The reuptake of neurotransmitters by dopamine, norepinephrine, and serotonin transporters during neuronal transmission requires a sodium gradient. An "ionic mode" of binding proposes that aspartate anchors the ligand's positive charge but ignores the direct role of sodium in ligand binding seen in the only representative structure, the prokaryotic leucine transporter LeuT. Here, we built structural models of human transporters of dopamine, norepinephrine, and serotonin using the LeuT structure. The ligand and sodium-binding sites are highly conserved. We examined the possibilities for ligand binding given the available experimental evidence, including examples of catechol-cation chelates in X-ray structures of protein and other complexes. We conclude that a "chelation mode" of binding with direct interaction between the catechol hydroxyls and sodium is a valid alternative, with consequences for pharmaceutical design. In the modeled serotonin transporter complexes, Y95 is placed where it could select for serotonin through hydrogen bonding to the indole nitrogen.
Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6 A, Turku, FI-20520 Finland. hxaard@abo.fi
Henri
H
Xhaard
Vera
V
Backström
Konstantin
K
Denessiouk
Mark S
MS
Johnson
D000595:Amino Acid Sequence; D015306:Biogenic Monoamines / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
D015306:Biogenic Monoamines; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D012964:Sodium