Saturday, November 23, 2024
No menu items!
HomeNatureStructure of the human dopamine transporter in complex with cocaine

Structure of the human dopamine transporter in complex with cocaine

  • Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. & Caron, M. G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–612 (1996).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Kristensen, A. S. et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev. 63, 585–640 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, R. et al. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc. Natl Acad. Sci. USA 103, 9333–9338 (2006).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Davis, S. E., Cirincione, A. B., Jimenez-Torres, A. C. & Zhu, J. The impact of neurotransmitters on the neurobiology of neurodegenerative diseases. Int. J. Mol. Sci. 24, 15340 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jones, S. R. et al. Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc. Natl Acad. Sci. USA 95, 4029–4034 (1998).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, K. H., Penmatsa, A. & Gouaux, E. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 521, 322–327 (2015).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Penmatsa, A., Wang, K. H. & Gouaux, E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503, 85–90 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Plenge, P. et al. The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nat. Commun. 12, 5063 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, D. & Gouaux, E. Illumination of serotonin transporter mechanism and role of the allosteric site. Sci. Adv. 7, eabl3857 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shahsavar, A. et al. Structural insights into the inhibition of glycine reuptake. Nature 591, 677–681 (2021).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei, Y. et al. Transport mechanism and pharmacology of the human GlyT1. Cell 187, 1719–1732 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Motiwala, Z. et al. Structural basis of GABA reuptake inhibition. Nature 606, 820–826 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nayak, S. R. et al. Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism. Nat. Struct. Mol. Biol. 30, 1023–1032 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, A. et al. Molecular basis for substrate recognition and transport of human GABA transporter GAT1. Nat. Struct. Mol. Biol. 30, 1012–1022 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yamashita, A., Singh, S. K., Kawate, T., Jin, Y. & Gouaux, E. Crystal structure of a bacterial homologue of Na+/Cl−-dependent neurotransmitter transporters. Nature 437, 215–223 (2005).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Loland, C. J. The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters. Biochim. Biophys. Acta 1850, 500–510 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rudnick, G. & Sandtner, W. Serotonin transport in the 21st century. J. Gen. Physiol. 151, 1248–1264 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Borre, L., Andreassen, T. F., Shi, L., Weinstein, H. & Gether, U. The second sodium site in the dopamine transporter controls cation permeation and is regulated by chloride. J. Biol. Chem. 289, 25764–25773 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tavoulari, S. et al. Two Na+ sites control conformational change in a neurotransmitter transporter homolog. J. Biol. Chem. https://doi.org/10.1074/jbc.M115.692012 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Nelson, P. J. & Rudnick, G. Coupling between platelet 5-hydroxytryptamine and potassium transport. J. Biol. Chem. 254, 10084–10089 (1979).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hellsberg, E. et al. Identification of the potassium-binding site in serotonin transporter. Proc. Natl Acad. Sci. USA 121, e2319384121 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schmidt, S. G. et al. The dopamine transporter antiports potassium to increase the uptake of dopamine. Nat. Commun. 13, 2446 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bhat, S. et al. Handling of intracellular K+ determines voltage dependence of plasmalemmal monoamine transporter function. eLife 10, e67996 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zeppelin, T., Ladefoged, L. K., Sinning, S., Periole, X. & Schiott, B. A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition. PLoS Comput. Biol. 14, e1005907 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pidathala, S., Mallela, A. K., Joseph, D. & Penmatsa, A. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. Nat. Commun. 12, 2199 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pörzgen, P., Park, S. K., Hirsh, J., Sonders, M. S. & Amara, S. G. The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines. Mol. Pharmacol. 59, 83–95 (2001).

    Article 
    PubMed 

    Google Scholar
     

  • Pugh, C. F., DeVree, B. T., Schmidt, S. G. & Loland, C. J. Pharmacological characterization of purified full-length dopamine transporter from Drosophila melanogaster. Cells 11, 3811 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, D., Zhao, Z., Tajkhorshid, E. & Gouaux, E. Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants. Proc. Natl Acad. Sci. USA 120, e2304602120 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chae, P. S. et al. A new class of amphiphiles bearing rigid hydrophobic groups for solubilization and stabilization of membrane proteins. Chemistry 18, 9485–9490 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bjerggaard, C. et al. Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions. J. Neurosci. 24, 7024–7036 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, L. B. et al. The role of N-glycosylation in function and surface trafficking of the human dopamine transporter. J. Biol. Chem. 279, 21012–21020 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Garcia-Olivares, J. et al. Gβγ subunit activation promotes dopamine efflux through the dopamine transporter. Mol. Psychiatry 22, 1673–1679 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fog, J. U. et al. Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron 51, 417–429 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cremona, M. L. et al. Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nat. Neurosci. 14, 469–477 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ehsan, M. et al. New malonate-derived tetraglucoside detergents for membrane protein stability. ACS Chem. Biol. 15, 1697–1707 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sørensen, L. et al. Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket. J. Biol. Chem. 287, 43694–43707 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Henry, L. K. 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. J. Biol. Chem. 281, 2012–2023 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Beuming, T. et al. The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat. Neurosci. 11, 780–789 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cheng, M. H. & Bahar, I. Molecular mechanism of dopamine transport by human dopamine transporter. Structure 23, 2171–2181 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Plenge, P. et al. Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter. J. Biol. Chem. 287, 39316–39326 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Salomon, K. et al. Dynamic extracellular vestibule of human SERT: unveiling druggable potential with high-affinity allosteric inhibitors. Proc. Natl Acad. Sci. USA 120, e2304089120 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Plenge, P. et al. The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter. Nat. Commun. 11, 1491 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coleman, J. A. et al. Chemical and structural investigation of the paroxetine-human serotonin transporter complex. eLife 9, e56427 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Laursen, L. et al. Cholesterol binding to a conserved site modulates the conformation, pharmacology, and transport kinetics of the human serotonin transporter. J. Biol. Chem. 293, 3510–3523 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nielsen, A. K. et al. Substrate-induced conformational dynamics of the dopamine transporter. Nat. Commun. 10, 2714 (2019).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bloch, J. S. et al. Development of a universal nanobody-binding Fab module for fiducial-assisted cryo-EM studies of membrane proteins. Proc. Natl Acad. Sci. USA 118, e2115435118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, S. et al. Fabs enable single particle cryoEM studies of small proteins. Structure 20, 582–592 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Esendir, E. et al. Extracellular loops of the serotonin transporter act as a selectivity filter for drug binding. J. Biol. Chem. 297, 100863 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Spyrakis, F. et al. The roles of water in the protein matrix: a largely untapped resource for drug discovery. J. Med. Chem. 60, 6781–6827 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Okorom, A. V. et al. Modifications to 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines that improve metabolic stability and retain an atypical DAT inhibitor profile. J. Med. Chem. https://doi.org/10.1021/acs.jmedchem.3c02037 (2024).

  • Chen, N., Zhen, J. & Reith, M. E. A. Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine. J. Neurochem. 89, 853–864 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mager, S. et al. Ion binding and permeation at the GABA transporter GAT1. J. Neurosci. 16, 5405–5414 (1996).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coleman, J. A. et al. Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. Nature 569, 141–145 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hong, W. C. & Amara, S. G. Membrane cholesterol modulates the outward facing conformation of the dopamine transporter and alters cocaine binding. J. Biol. Chem. 285, 32616–32626 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frangos, Z. J. et al. Membrane cholesterol regulates inhibition and substrate transport by the glycine transporter, GlyT2. Life Sci. Alliance 6, e202201708 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Merkle, P. S. et al. Substrate-modulated unwinding of transmembrane helices in the NSS transporter LeuT. Sci. Adv. 4, eaar6179 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zou, M. F. et al. Structure–activity relationship studies on a series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes as novel atypical dopamine transporter (DAT) inhibitors for the treatment of cocaine use disorders. J. Med. Chem. 60, 10172–10187 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Loland, C. J. et al. R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol. Psychiatry 72, 405–413 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Loland, C. J. et al. Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Mol. Pharmacol. 73, 813–823 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75, 861–877 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dewar, M. J. S., Zoebisch, E. G., Healy, E. F. & Stewart, J. J. P. Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. J. Am. Chem. Soc. 107, 3902–3909 (1985).

    Article 

    Google Scholar
     

  • Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Shelley, J. C. et al. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules. J. Comput. Aided Mol. Des. 21, 681–691 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Lomize, M. A., Pogozheva, I. D., Joo, H., Mosberg, H. I. & Lomize, A. L. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 40, D370–D376 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vanommeslaeghe, K. et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31, 671–690 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, J. et al. CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J. Chem. Theory Comput. 12, 405–413 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Klauda, J. B. et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 114, 7830–7843 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. https://doi.org/10.1063/1.2408420 (2007).

  • Nosé, S. & Klein, M. L. Constant pressure molecular dynamics for molecular systems. Mol. Phys. 50, 1055–1076 (1983).

    Article 
    ADS 

    Google Scholar
     

  • Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Hess, B., Bekker, H., Berendsen, H. J. C. & Fraaije, J. G. E. M. LINCS: a linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997).

    Article 
    CAS 

    Google Scholar
     

  • Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nielsen, J. C. et al. MD simulations files for: structure of the human dopamine transporter in complex with cocaine. Zenodo https://doi.org/10.5281/zenodo.10804003 (2024).

  • RELATED ARTICLES

    Most Popular

    Recent Comments