Structural insights into the inhibition of glycine reuptake.
Binding Sites
Biological Transport
/ drug effects
Crystallography
Glycine
/ metabolism
Glycine Plasma Membrane Transport Proteins
/ antagonists & inhibitors
Humans
Models, Molecular
Piperazines
/ chemistry
Protein Binding
Protein Conformation
Protein Stability
Single-Domain Antibodies
Sulfones
/ chemistry
Synchrotrons
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
29
05
2020
accepted:
20
01
2021
pubmed:
5
3
2021
medline:
8
1
2022
entrez:
4
3
2021
Statut:
ppublish
Résumé
The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine
Identifiants
pubmed: 33658720
doi: 10.1038/s41586-021-03274-z
pii: 10.1038/s41586-021-03274-z
doi:
Substances chimiques
(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
0
Glycine Plasma Membrane Transport Proteins
0
Piperazines
0
SLC6A9 protein, human
0
Single-Domain Antibodies
0
Sulfones
0
Glycine
TE7660XO1C
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
677-681Références
Harvey, R. J. & Yee, B. K. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat. Rev. Drug Discov. 12, 866–885 (2013).
pubmed: 24172334
doi: 10.1038/nrd3893
Grenningloh, G. et al. The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature 328, 215–220 (1987).
pubmed: 3037383
doi: 10.1038/328215a0
Johnson, J. W. & Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325, 529–531 (1987).
pubmed: 2433595
doi: 10.1038/325529a0
Cioffi, C. L. Glycine transporter-1 inhibitors: a patent review (2011–2016). Expert Opin. Ther. Pat. 28, 197–210 (2018).
pubmed: 29338548
doi: 10.1080/13543776.2018.1429408
Kristensen, A. S. et al. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev. 63, 585–640 (2011).
pubmed: 21752877
doi: 10.1124/pr.108.000869
Gomeza, J. et al. Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition. Neuron 40, 785–796 (2003).
pubmed: 14622582
doi: 10.1016/S0896-6273(03)00672-X
Cubelos, B., Giménez, C. & Zafra, F. Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. Cereb. Cortex 15, 448–459 (2005).
pubmed: 15749988
doi: 10.1093/cercor/bhh147
Cubelos, B., González-González, I. M., Giménez, C. & Zafra, F. The scaffolding protein PSD-95 interacts with the glycine transporter GLYT1 and impairs its internalization. J. Neurochem. 95, 1047–1058 (2005).
pubmed: 16271045
doi: 10.1111/j.1471-4159.2005.03438.x
Kantrowitz, J. T. & Javitt, D. C. N-methyl-D-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res. Bull. 83, 108–121 (2010).
pubmed: 20417696
pmcid: 2941541
doi: 10.1016/j.brainresbull.2010.04.006
Pinard, E., Borroni, E., Koerner, A., Umbricht, D. & Alberati, D. Glycine transporter type I (GlyT1) inhibitor, bitopertin: a journey from lab to patient. CHIMIA Int. J. Chem. 72, 477–484 (2018).
doi: 10.2533/chimia.2018.477
Shim, S. S., Hammonds, M. D. & Kee, B. S. Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site. Eur. Arch. Psychiatry Clin. Neurosci. 258, 16–27 (2007).
pubmed: 17901997
doi: 10.1007/s00406-007-0757-8
Pinard, E. et al. Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia. J. Med. Chem. 53, 4603–4614 (2010).
pubmed: 20491477
doi: 10.1021/jm100210p
Krystal, J. H. et al. Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. Drug Discov. Today 14, 690–697 (2009).
pubmed: 19460458
pmcid: 2898127
doi: 10.1016/j.drudis.2009.05.002
D’Souza, D. C. et al. Dose-related target occupancy and effects on circuitry, behavior, and neuroplasticity of the glycine transporter-1 inhibitor PF-03463275 in healthy and schizophrenia subjects. Biol. Psychiatry 84, 413–421 (2018).
pubmed: 29499855
pmcid: 6068006
doi: 10.1016/j.biopsych.2017.12.019
Jardetzky, O. Simple allosteric model for membrane pumps. Nature 211, 969–970 (1966).
pubmed: 5968307
doi: 10.1038/211969a0
Kazmier, K. et al. Conformational dynamics of ligand-dependent alternating access in LeuT. Nat. Struct. Mol. Biol. 21, 472–479 (2014).
pubmed: 24747939
pmcid: 4050370
doi: 10.1038/nsmb.2816
Malinauskaite, L. et al. A mechanism for intracellular release of Na
pubmed: 25282149
pmcid: 4346222
doi: 10.1038/nsmb.2894
Penmatsa, A., Wang, K. H. & Gouaux, E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503, 85–90 (2013).
pubmed: 24037379
pmcid: 3904663
doi: 10.1038/nature12533
Coleman, J. A. et al. Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. Nature 569, 141–145 (2019).
pubmed: 31019304
pmcid: 6750207
doi: 10.1038/s41586-019-1135-1
Gotfryd, K. et al. X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. Nat. Commun. 11, 1005 (2020).
pubmed: 32081981
pmcid: 7035281
doi: 10.1038/s41467-020-14735-w
Singh, S. K., Yamashita, A. & Gouaux, E. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448, 952–956 (2007).
pubmed: 17687333
doi: 10.1038/nature06038
Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339 (2016).
pubmed: 27049939
pmcid: 4898786
doi: 10.1038/nature17629
Malinauskaite, L. et al. A conserved leucine occupies the empty substrate site of LeuT in the Na
pubmed: 27221344
pmcid: 4894957
doi: 10.1038/ncomms11673
Alberati, D. et al. Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 62, 1152–1161 (2012).
pubmed: 22138164
doi: 10.1016/j.neuropharm.2011.11.008
Pinard, E. et al. Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors. Bioorg. Med. Chem. Lett. 20, 6960–6965 (2010).
pubmed: 20974532
doi: 10.1016/j.bmcl.2010.09.124
Jolidon, S., Narquizian, R., Norcross, R. D. & Pinard, E. Heterocyclic substituted phenyl methanones as inhibitors of the glycine transporter 1. WIPO patent WO/2006/082001 (2006).
Brown, A. et al. Discovery and SAR of Org 24598—a selective glycine uptake inhibitor. Bioorg. Med. Chem. Lett. 11, 2007–2009 (2001).
pubmed: 11454468
doi: 10.1016/S0960-894X(01)00355-9
Zimmermann, I. et al. Synthetic single domain antibodies for the conformational trapping of membrane proteins. eLife 7, e34317 (2018).
pubmed: 29792401
pmcid: 5967865
doi: 10.7554/eLife.34317
Abramson, J. & Wright, E. M. Structure and function of Na
pubmed: 19631523
pmcid: 3496787
doi: 10.1016/j.sbi.2009.06.002
LeVine, M. V. et al. The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor. Proc. Natl Acad. Sci. USA 116, 15947–15956 (2019).
pubmed: 31324743
pmcid: 6689989
doi: 10.1073/pnas.1903020116
Carland, J. E. et al. Molecular determinants for substrate interactions with the glycine transporter GlyT2. ACS Chem. Neurosci. 9, 603–614 (2018).
pubmed: 29120604
doi: 10.1021/acschemneuro.7b00407
Focht, D. et al. A non-helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition. EMBO J. 40, e105164 (2020).
pubmed: 33155685
pmcid: 7780149
Jaeger, K. et al. Structural basis for allosteric ligand recognition in the human CC chemokine receptor 7. Cell 178, 1222–1230 (2019).
pubmed: 31442409
pmcid: 6709783
doi: 10.1016/j.cell.2019.07.028
Vandenberg, R. J., Shaddick, K. & Ju, P. Molecular basis for substrate discrimination by glycine transporters. J. Biol. Chem. 282, 14447–14453 (2007).
pubmed: 17383967
doi: 10.1074/jbc.M609158200
Werdehausen, R. et al. Lidocaine metabolites inhibit glycine transporter 1: a novel mechanism for the analgesic action of systemic lidocaine? Anesthesiology 116, 147–158 (2012).
pubmed: 22133759
doi: 10.1097/ALN.0b013e31823cf233
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).
pubmed: 17698848
doi: 10.1074/jbc.M704456200
Bugarski-Kirola, D. et al. Bitopertin in negative symptoms of schizophrenia-results from the phase III FlashLyte and DayLyte studies. Biol. Psychiatry 82, 8–16 (2017).
pubmed: 28117049
doi: 10.1016/j.biopsych.2016.11.014
Martin-Facklam, M. et al. Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers. Neuropsychopharmacology 38, 504–512 (2013).
pubmed: 23132267
doi: 10.1038/npp.2012.212
Weber, F. et al. Brain shuttle antibody for Alzheimer’s disease with attenuated peripheral effector function due to an inverted binding mode. Cell Rep. 22, 149–162 (2018).
pubmed: 29298417
doi: 10.1016/j.celrep.2017.12.019
Olivares, L., Aragón, C., Giménez, C. & Zafra, F. The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter. J. Biol. Chem. 270, 9437–9442 (1995).
pubmed: 7721869
doi: 10.1074/jbc.270.16.9437
Gati, C. et al. Serial crystallography on in vivo grown microcrystals using synchrotron radiation. IUCrJ. 1, 87–94 (2014).
pubmed: 25075324
pmcid: 4062088
doi: 10.1107/S2052252513033939
Zander, U. et al. MeshAndCollect: an automated multi-crystal data-collection workflow for synchrotron macromolecular crystallography beamlines. Acta Crystallogr. D 71, 2328–2343 (2015).
pubmed: 26527148
pmcid: 4631482
doi: 10.1107/S1399004715017927
Popov, A. N. & Bourenkov, G. Dozor (European Synchrotron Radiation Facility, 2016).
Tange, O. GNU Parallel: the command-line power tool. The USENIX Magazine 36, 42–47 (2011).
Kabsch, W. XDS. Acta Crystallogr. D 66, 125–132 (2010).
pubmed: 20124692
pmcid: 2815665
doi: 10.1107/S0907444909047337
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).
pubmed: 20383002
pmcid: 2852313
doi: 10.1107/S0907444910007493
Bricogne, G. et al. BUSTER v.2.10.3 (Global Phasing, 2019).
Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D 74, 519–530 (2018).
doi: 10.1107/S2059798318002425
Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D 75, 861–877 (2019).
doi: 10.1107/S2059798319011471
Hattori, M., Hibbs, R. E. & Gouaux, E. A fluorescence-detection size-exclusion chromatography-based thermostability assay for membrane protein precrystallization screening. Structure 20, 1293–1299 (2012).
pubmed: 22884106
pmcid: 3441139
doi: 10.1016/j.str.2012.06.009
Alexandrov, A. I., Mileni, M., Chien, E. Y. T., Hanson, M. A. & Stevens, R. C. Microscale fluorescent thermal stability assay for membrane proteins. Structure 16, 351–359 (2008).
pubmed: 18334210
doi: 10.1016/j.str.2008.02.004
Hawkins, P. C. D., Skillman, A. G. & Nicholls, A. Comparison of shape-matching and docking as virtual screening tools. J. Med. Chem. 50, 74–82 (2007).
pubmed: 17201411
doi: 10.1021/jm0603365
Molecular Operating Environment (MOE) 2019.01 (Chemical Computing Group, 2019).
Jones, G., Willett, P., Glen, R. C., Leach, A. R. & Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 267, 727–748 (1997).
pubmed: 9126849
doi: 10.1006/jmbi.1996.0897
Mosca, R. & Schneider, T. R. RAPIDO: a web server for the alignment of protein structures in the presence of conformational changes. Nucleic Acids Res. 36, W42–W46 (2008).
pubmed: 18460546
pmcid: 2447786
doi: 10.1093/nar/gkn197
Caulfield, W. L. et al. The first potent and selective inhibitors of the glycine transporter type 2. J. Med. Chem. 44, 2679–2682 (2001).
pubmed: 11495577
doi: 10.1021/jm0011272
Madeira, F. et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 47 (W1), W636–W641 (2019).
pubmed: 30976793
pmcid: 6602479
doi: 10.1093/nar/gkz268
Ashkenazy, H. et al. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 44 (W1), W344–W350 (2016).
pubmed: 27166375
pmcid: 4987940
doi: 10.1093/nar/gkw408
Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D 67, 235–242 (2011).
pubmed: 21460441
pmcid: 3069738
doi: 10.1107/S0907444910045749
Kantcheva, A. K. et al. Chloride binding site of neurotransmitter sodium symporters. Proc. Natl Acad. Sci. USA 110, 8489–8494 (2013).
pubmed: 23641004
pmcid: 3666746
doi: 10.1073/pnas.1221279110
Zhang, Y.-W. et al. Chloride-dependent conformational changes in the GlyT1 glycine transporter. Proc. Natl Acad. Sci. USA (in the press) (2021).
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).
pubmed: 19074341
pmcid: 2832577
doi: 10.1126/science.1166777
Diederichs, K., & Karplus, P. A. Improved R-factors for diffraction data analysis in macromolecular crystallography. Nat. Struct. Mol. Biol. 4, 269–275 (1997).
doi: 10.1038/nsb0497-269
Diederichs, K., & Karplus, P. A. Linking crystallographic model and data quality. Science. 336, 1030–1033 (2012).
pubmed: 22628654
pmcid: 3457925
doi: 10.1126/science.1218231