A homology model of SERT based on the LeuTAa template

Ravna, Aina Westrheim; Jarończyk, Małgorzata; Sylte, Ingebrigt

doi:10.1016/j.bmcl.2006.08.028

Cited by 26 publications

(22 citation statements)

References 37 publications

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“…Specifically lacking are models that explicitly compute the nature and relative contributions of interactions occurring between the inhibitor and transporter, assess the ligand surface area buried by that interaction, and account for SERT conformational transitions stabilized by the ligand. A homology model for the interaction of SERT with inhibitors was recently proposed, based on bacterial leucine transporter (Ravna et al, 2006a). More recently, cocrystallization of antidepressant with the homologous LeuT was reported (Singh et al, 2007;Zhou et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Of these, the most homologous transporter to SERT is the bacterial leucine transporter LeuT (Yamashita et al, 2005). A three-dimensional model of SERT based on the published crystal structure of LeuT places several key amino acid residues that interact with SERT inhibitors along the proposed substrate permeation path (Ravna et al, 2006a).Recently, crystal structures of LeuT in complex with highaffinity SERT inhibitors were reported (Singh et al, 2007;Zhou et al, 2007). These structures identify the substrate (leucine) and inhibitor binding sites as nonoverlapping.…”

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confidence: 99%

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Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

Martin

Henningsen²,

Suen³

et al. 2008

J Pharmacol Exp Ther

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Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [ 3 H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26°C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal ⅐ mol Ϫ1 ), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (⌬H O ) and entropy (ϪT⌬S O )contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% ⌬G O ) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.Inhibitors of the serotonin transporter (SERT) have long been in clinical use for treatment of depression and anxiety, predating even the molecular identification of the target (Blakely et al., 1991). As such, SERT is the target of a large number of clinically proven drugs from diverse chemotypes (Fig. 1) that act by blocking transit of 5-hydroytryptamine (serotonin) (5-HT) through the transporter. Many reports describe the equilibrium binding properties of members of this class of drugs with SERT as well as potency for inhibition of 5-HT reuptake (Blakely et al., 1994;Tatsumi et al., 1997;Nemeroff and Owens, 2003;Rothman and Baumann, 2003). Although the three-dimensional structure of SERT has not yet been elucidated, crystal structures have been determined for other members of the 12 transmembrane domain major facilitator superfamily. Of these, the most homologous transporter to SERT is the bacterial leucine transporter LeuT (Yamashita et al., 2005). A three-dimensional model of SERT based on the published crystal structure of LeuT places several key amino acid residues that interact with SERT inhibitors along the proposed substrate permeation path (Ravna et al., 2006a).Recently, crystal structures of LeuT in complex with highaffinity SERT inhibitors wer...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

Martin

Henningsen²,

Suen³

et al. 2008

J Pharmacol Exp Ther

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“…The only major difference among these residues is found in the monoamine transporters, which contain an Asp in the position equivalent to Gly24 in LeuT. Homology models of SERT (Henry et al, 2006b;Ravna et al, 2006;Celik et al, 2008b;Forrest et al, 2008;Andersen et al, 2009b) and DAT ( Huang and Zhan, 2007;Beuming et al, 2008;Jin et al, 2008b) suggest that the ␤-carboxyl group of Asp compensates for the inability of the monoamine substrates to interact with Na ϩ in the Na1 site because these lack a negatively charged carboxyl group, in contrast to GABA and glycine as mentioned previously (Figs. 5 and 7).…”

Section: The Slc6 Neurotransmitter Transportersmentioning

confidence: 99%

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

et al. 2011

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“…This structure and subsequent structures (8)(9)(10)(11)(12) have served as templates for the exploration of NSS function in a structural context (7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Computational studies combined with binding and flux experiments have led to proposing a second substrate (S2) site and a molecular mechanism of Na + -substrate symport that depends on the allosteric interaction of substrate molecules in the two high-affinity sites (7,11,18,23,27).…”

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confidence: 99%

Chloride binding site of neurotransmitter sodium symporters

Kantcheva

Quick

Shi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

100

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Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding.

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A homology model of SERT based on the LeuTAa template

Cited by 26 publications

References 37 publications

Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

Chloride binding site of neurotransmitter sodium symporters

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