Structure and localisation of drug binding sites on neurotransmitter transporters

The dopamine (DAT), serotontin (SERT) and noradrenalin (NET) transporters are molecular targets for different classes of psychotropic drugs. The crystal structure of Aquifex aeolicus LeuTAa was used as a template for molecular modeling of DAT, SERT and NET, and two putative drug binding sites (pocket 1 and 2) in each transporter were identified. Cocaine was docked into binding pocket 1 of DAT, corresponding to the leucine binding site in LeuTAa, which involved transmembrane helices (TMHs) 1, 3, 6 and 8. Clomipramine was docked into binding pocket 2 of DAT, involving TMHs 1, 3, 6, 10 and 11, and extracellular loops 4 and 6, corresponding to the clomipramine binding site in a crystal structure of a LeuTAa–clomipramine complex. The structures of the proposed cocaine- and tricyclic antidepressant-binding sites may be of particular interest for the design of novel DAT interacting ligands.

[1]  C. Sander,et al.  Errors in protein structures , 1996, Nature.

[2]  K. Lesch,et al.  Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions , 2002, Neuroscience.

[3]  R. Blakely,et al.  Pharmacological profile of antidepressants and related compounds at human monoamine transporters. , 1997, European journal of pharmacology.

[4]  Da-Neng Wang,et al.  LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake , 2007, Science.

[5]  S Kitayama,et al.  Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Geoffrey Chang,et al.  Flexibility in the ABC transporter MsbA: Alternating access with a twist , 2007, Proceedings of the National Academy of Sciences.

[7]  Barry Honig,et al.  Identification of a chloride ion binding site in Na+/Cl−-dependent transporters , 2007, Proceedings of the National Academy of Sciences.

[8]  J. Schildkraut,et al.  The catecholamine hypothesis of affective disorders: a review of supporting evidence. , 1965, The American journal of psychiatry.

[9]  Henri Xhaard,et al.  Coordination of Na+ by Monoamine Ligands in Dopamine, Norepinephrine, and Serotonin Transporters , 2008, J. Chem. Inf. Model..

[10]  G. Uhl,et al.  Dopamine transporter: transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition. , 1999, Molecular pharmacology.

[11]  A. Ravna,et al.  A putative three-dimensional arrangement of the human serotonin transporter transmembrane helices: a tool to aid experimental studies. , 2001, Journal of molecular graphics & modelling.

[12]  Ingebrigt Sylte,et al.  Putative drug binding conformations of monoamine transporters. , 2006, Bioorganic & medicinal chemistry.

[13]  Ingebrigt Sylte,et al.  Molecular model of the neural dopamine transporter , 2003, J. Comput. Aided Mol. Des..

[14]  G. Rudnick,et al.  The Third Transmembrane Domain of the Serotonin Transporter Contains Residues Associated with Substrate and Cocaine Binding* , 1997, The Journal of Biological Chemistry.

[15]  R. Blakely,et al.  High Affinity Recognition of Serotonin Transporter Antagonists Defined by Species-scanning Mutagenesis , 1998, The Journal of Biological Chemistry.

[16]  Harel Weinstein,et al.  A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na+ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function , 2006, Molecular Pharmacology.

[17]  Eric Gouaux,et al.  Antidepressant binding site in a bacterial homologue of neurotransmitter transporters , 2007, Nature.

[18]  T. Yeates,et al.  Verification of protein structures: Patterns of nonbonded atomic interactions , 1993, Protein science : a publication of the Protein Society.

[19]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[20]  Eric L. Barker,et al.  Transmembrane Domain I Contributes to the Permeation Pathway for Serotonin and Ions in the Serotonin Transporter , 1999, The Journal of Neuroscience.

[21]  A. Ravna,et al.  The molecular interactions of buspirone analogues with the serotonin transporter. , 2008, Bioorganic & medicinal chemistry.

[22]  O. V. Mortensen,et al.  Species‐scanning mutagenesis of the serotonin transporter reveals residues essential in selective, high‐affinity recognition of antidepressants , 2001, Journal of neurochemistry.

[23]  G. Uhl,et al.  Dopamine transporter mutants, small molecules, and approaches to cocaine antagonist/dopamine transporter disinhibitor development. , 1998, Methods in enzymology.

[24]  A. Ravna.  Three-dimensional models of neurotransmitter transporters and their interactions with cocaine and S-citalopram , 2006, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[25]  R. Abagyan,et al.  Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. , 1994, Journal of molecular biology.

[26]  B. Elfving,et al.  The Chicken Serotonin Transporter Discriminates between Serotonin-selective Reuptake Inhibitors , 2004, Journal of Biological Chemistry.

[27]  Ingebrigt Sylte,et al.  Molecular Mechanism of Citalopram and Cocaine Interactions with Neurotransmitter Transporters , 2003, Journal of Pharmacology and Experimental Therapeutics.

[28]  A. Ravna,et al.  A homology model of SERT based on the LeuT(Aa) template. , 2006, Bioorganic & medicinal chemistry letters.

[29]  R. Blakely,et al.  Tyr-95 and Ile-172 in Transmembrane Segments 1 and 3 of Human Serotonin Transporters Interact to Establish High Affinity Recognition of Antidepressants* , 2006, Journal of Biological Chemistry.

[30]  G. Heijne.  The distribution of positively charged residues in bacterial inner membrane proteins correlates with the trans‐membrane topology , 1986, The EMBO journal.

[31]  M. Bardo,et al.  Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. , 1998, Critical reviews in neurobiology.

[32]  Finn Drabløs,et al.  Homology-based modelling of targets for rational drug design. , 2004, Mini reviews in medicinal chemistry.

[33]  I. Sora,et al.  Cocaine, reward, movement and monoamine transporters , 2002, Molecular Psychiatry.

[34]  Bruno Giros,et al.  Determination of Residues in the Norepinephrine Transporter That Are Critical for Tricyclic Antidepressant Affinity* , 2001, The Journal of Biological Chemistry.

[35]  K. Gundertofte,et al.  Homology Modeling of the Serotonin Transporter: Insights into the Primary Escitalopram‐binding Site , 2007, ChemMedChem.

[36]  B. S. Park,et al.  Importance of valine at position 152 for the substrate transport and 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane binding of dopamine transporter. , 2000, Molecular pharmacology.

[37]  Ruben Abagyan,et al.  ICM—A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation , 1994, J. Comput. Chem..

[38]  G. Uhl,et al.  Dopamine transporter tryptophan mutants highlight candidate dopamine- and cocaine-selective domains. , 2000, Molecular pharmacology.

[39]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[40]  H. Manji,et al.  Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. , 2001, Psychopharmacology bulletin.

[41]  H. Kaback,et al.  From membrane to molecule to the third amino acid from the left with a membrane transport protein , 1997, Quarterly Reviews of Biophysics.