X-ray structures of LeuT in substrate-free outward-open and apo inward-open states (original) (raw)

• Hertting, G. & Axelrod, J. Fate of tritiated noradrenaline at the sympathetic nerve-endings. Nature 192, 172–173 (1961)
  Article ADS CAS Google Scholar
• Nelson, N. The family of Na+/Cl− neurotransmitter transporters. J. Neurochem. 71, 1785–1803 (1998)
  Article CAS Google Scholar
• Saier, M. H. J. A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol. Mol. Biol. Rev. 64, 354–411 (2000)
  Article CAS Google Scholar
• Hahn, M. K. & Blakely, R. D. Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenomics J. 2, 217–235 (2002)
  Article CAS Google Scholar
• Klimek, V. et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J. Neurosci. 17, 8451–8458 (1997)
  Article CAS Google Scholar
• Richerson, G. B. & Wu, Y. Role of the GABA transporter in epilepsy. Adv. Exp. Med. Biol. 548, 76–91 (2004)
  Article CAS Google Scholar
• Amara, S. G. & Sonders, M. S. Neurotransmitter transporters as molecular targets for addictive drugs. Drug Alcohol Depend. 51, 87–96 (1998)
  Article CAS Google Scholar
• Mitchell, P. A general theory of membrane transport from studies of bacteria. Nature 180, 134–136 (1957)
  Article ADS CAS Google Scholar
• Jardetzky, O. Simple allosteric model for membrane pumps. Nature 211, 969–970 (1966)
  Article ADS CAS 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 Google Scholar
• Singh, S., Yamashita, A. & Gouaux, E. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448, 952–956 (2007)
  Article ADS CAS Google Scholar
• Singh, S. K., Piscitelli, C. L., Yamashita, A. & Gouaux, E. A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322, 1655–1661 (2008)
  Article ADS CAS Google Scholar
• Zhou, Z. et al. LeuT-desipramine structure reveals how antidepressants block neurotransmitter uptake. Science 317, 1390–1393 (2007)
  Article ADS CAS Google Scholar
• Zhou, Z. et al. Antidepressant specificity of serotonin transporter suggested by three LeuT–SSRI structures. Nature Struct. Mol. Biol. 16, 652–657 (2009)
  Article CAS Google Scholar
• Weyand, S. et al. Structure and molecular mechanism of a nucleobase–cation–symport-1 family transporter. Science 322, 709–713 (2008)
  Article ADS CAS Google Scholar
• Faham, S. et al. The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321, 810–814 (2008)
  Article ADS CAS Google Scholar
• Shaffer, P. L., Goehring, A., Shankaranarayanan, A. & Gouaux, E. Structure and mechanism of a Na+-independent amino acid transporter. Science 325, 1010–1014 (2009)
  Article ADS CAS Google Scholar
• Shimamura, T. et al. Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1. Science 328, 470–473 (2010)
  Article ADS CAS Google Scholar
• Krishnamurthy, H., Piscitelli, C. L. & Gouaux, E. Unlocking the molecular secrets of sodium-coupled transporters. Nature 459, 347–355 (2009)
  Article ADS CAS Google Scholar
• Shaikh, S. A. & Tajkhorshid, E. Modeling and dynamics of the inward-facing state of a Na+/Cl− dependent neurotransmitter transporter homologue. PLOS Comput. Biol. 6, e1000905 (2010)
  Article ADS Google Scholar
• Claxton, D. P. et al. Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters. Nature Struct. Mol. Biol. 17, 822–829 (2010)
  Article CAS Google Scholar
• Forrest, L. R. et al. Mechanism for alternating access in neurotransmitter transporters. Proc. Natl Acad. Sci. USA 105, 10338–10343 (2008)
  Article ADS CAS Google Scholar
• Zhao, Y. et al. Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Nature 465, 188–193 (2010)
  Article ADS CAS Google Scholar
• Boudker, O. & Verdon, G. Structural perspectives on secondary active transporters. Trends Pharmacol. Sci. 31, 418–426 (2010)
  Article CAS Google Scholar
• Piscitelli, C. L., Krishnamurthy, H. & Gouaux, E. Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site. Nature 468, 1129–1132 (2010)
  Article ADS CAS Google Scholar
• Kawate, T. & Gouaux, E. Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins. Structure 14, 673–681 (2006)
  Article CAS Google Scholar
• Kniazeff, J. et al. An intracellular interaction network regulates conformational transitions in the dopamine transporter. J. Biol. Chem. 283, 17691–17701 (2008)
  Article CAS Google Scholar
• Loland, C. J., Norregaard, L., Litman, T. & Gether, U. Generation of an activating Zn2+ switch in the dopamine transporter: mutation of an intracellular tyrosine constitutively alters the conformational equilibrium of the transport cycle. Proc. Natl Acad. Sci. USA 99, 1683–1688 (2002)
  Article ADS CAS Google Scholar
• Celik, L., Schiott, B. & Tajkhorshid, E. Substrate binding and formation of an occluded state in the leucine transporter. Biophys. J. 94, 1600–1612 (2008)
  Article CAS Google Scholar
• Harding, M. M. Small revisions to predicted distances around metal sites in proteins. Acta Crystallogr. D 62, 678–682 (2006)
  Article Google Scholar
• Zhang, Y.-W. & Rudnick, G. The cytoplasmic substrate permeation pathway of serotonin transporter. J. Biol. Chem. 281, 36213–36220 (2006)
  Article CAS Google Scholar
• Rudnick, G. The cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry 50, 7462–7475 (2011)
  Article CAS Google Scholar
• Ben-Yona, A. & Kanner, B. I. Transmembrane domain 8 of the γ-aminobutyric acid transporter GAT-1 lines a cytoplasmic accessibility pathway into its binding pocket. J. Biol. Chem. 284, 9727–9732 (2009)
  Article CAS Google Scholar
• Tao, Z., Zhang, Y. W., Agyiri, A. & Rudnick, G. Ligand effects on cross-linking support a conformational mechanism for serotonin transport. J. Biol. Chem. 284, 33807–33814 (2009)
  Article CAS Google Scholar
• Rosenberg, A. & Kanner, B. I. The substrates of the γ-aminobutyric acid transporter GAT-1 induce structural rearrangements around the interface of transmembrane domains 1 and 6. J. Biol. Chem. 283, 14376–14383 (2008)
  Article CAS Google Scholar
• Henry, L. K., Adkins, E. M., Han, Q. & Blakely, R. D. Serotonin and cocaine-sensitive inactivation of human serotonin transporters by methanethiosulfonates targeted to transmembrane domain I. J. Biol. Chem. 278, 37052–37063 (2003)
  Article CAS Google Scholar
• Zomot, E. & Kanner, B. I. The interaction of the γ-aminobutyric acid transporter GAT-1 with the neurotransmitter is selectively impaired by sulfhydryl modification of a conformationally sensitive cysteine residue engineered into extracellular loop IV. J. Biol. Chem. 278, 42950–42958 (2003)
  Article CAS Google Scholar
• Mitchell, S. M., Lee, E., Garcia, M. L. & Stephan, M. M. Structure and function of extracellular loop 4 of the serotonin transporter as revealed by cysteine-scanning mutagenesis. J. Biol. Chem. 279, 24089–24099 (2004)
  Article CAS Google Scholar
• Smicun, Y., Campbell, S. D., Chen, M. A., Gu, H. & Rudnick, G. The role of external loop regions in serotonin transport. Loop scanning mutagenesis of the serotonin transporter external domain. J. Biol. Chem. 274, 36058–36064 (1999)
  Article CAS Google Scholar
• Hirayama, B. A., Diez-Sampedro, A. & Wright, E. M. Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl−/GABA (hGAT1) cotransporters. Br. J. Pharmacol. 134, 484–495 (2001)
  Article CAS Google Scholar
• Jacobs, M. T., Zhang, Y. W., Campbell, S. D. & Rudnick, G. Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. J. Biol. Chem. 282, 29441–29447 (2007)
  Article CAS Google Scholar
• Shi, L., Quick, M., Zhao, Y., Weinstein, H. & Javitch, J. A. The mechanism of a neurotransmitter:sodium symporter-inward release of Na+ and substrate is triggered by a substrate in a second binding site. Mol. Cell 30, 667–677 (2008)
  Article CAS Google Scholar
• Zhao, Y. et al. Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue. Nature 474, 109–113 (2011)
  Article CAS Google Scholar
• Pantanowitz, S., Bendahan, A. & Kanner, B. I. Only one of the charged amino acids located in the transmembrane α-helices of the γ-aminobutyric acid transporter (subtype A) is essential for its activity. J. Biol. Chem. 268, 3222–3225 (1993)
  CAS PubMed Google Scholar
• Bennett, E. R., Su, H. & Kanner, B. I. Mutation of arginine 44 of GAT-1, a (Na+ + Cl−)-coupled γ-aminobutyric acid transporter from rat brain, impairs net flux but not exchange. J. Biol. Chem. 275, 34106–34113 (2000)
  Article CAS Google Scholar
• Loland, C. J., Granas, C., Javitch, J. A. & Gether, U. Identification of intracellular residues in the dopamine transporter critical for regulation of transporter conformation and cocaine binding. J. Biol. Chem. 279, 3228–3238 (2004)
  Article CAS Google Scholar
• Chen, N., Rickey, J., Berfield, J. L. & Reith, M. E. Aspartate 345 of the dopamine transporter is critical for conformational changes in substrate translocation and cocaine binding. J. Biol. Chem. 279, 5508–5519 (2004)
  Article CAS Google Scholar
• Watanabe, A. et al. The mechanism of sodium and substrate release from the binding pocket of vSGLT. Nature 468, 988–991 (2010)
  Article ADS CAS Google Scholar
• Quick, M. et al. State-dependent conformations of the translocation pathway in the tyrosine transporter Tyt1, a novel neurotransmitter:sodium symporter from Fusobacterium nucleatum . J. Biol. Chem. 281, 26444–26454 (2006)
  Article CAS Google Scholar
• Shi, L. & Weinstein, H. Conformational rearrangements to the intracellular open states of the LeuT and ApcT transporters are modulated by common mechanisms. Biophys. J. 99, L103–L105 (2010)
  Article CAS Google Scholar
• Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)
  Article CAS Google Scholar
• Collaborative Computational Project 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)
• Matthews, B. W. Solvent content of protein crystals. J. Mol. Biol. 33, 491–497 (1968)
  Article CAS Google Scholar
• McCoy, A. J. Solving structures of protein complexes by molecular replacement with Phaser. Acta Crystallogr. D 63, 32–41 (2007)
  Article CAS Google Scholar
• Kopp, J. & Schwede, T. The SWISS-MODEL Repository: new features and functionalities. Nucleic Acids Res. 34, D315–D318 (2006)
  Article CAS Google Scholar
• Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)
  Article Google Scholar
• Adams, P. D. et al. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr. D 58, 1948–1954 (2002)
  Article Google Scholar
• Painter, J. & Merritt, E. A. Optimal description of a protein structure in terms of multiple groups undergoing TLS motion. Acta Crystallogr. D 62, 439–450 (2006)
  Article Google Scholar
• Terwilliger, T. C. Using prime-and-switch phasing to reduce model bias in molecular replacement. Acta Crystallogr. D 60, 2144–2149 (2004)
  Article Google Scholar
• Kelley, L. A. & Sternberg, M. J. Protein structure prediction on the Web: a case study using the Phyre server. Nature Protocols 4, 363–371 (2009)
  Article CAS Google Scholar
• Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010)
  Article CAS Google Scholar