title: Structural Integrity of the A147T Polymorph of Mammalian TSPO.
abstract: Ligands of the transmembrane protein TSPO are used for imaging of brain inflammation, but a common polymorphism in TSPO complicates their application to humans. Here we determined the three-dimensional structure and side-chain dynamics of the A147T polymorph of mammalian TSPO in complex with the first-generation ligand PK11195. We show that A147T TSPO is able to retain the same structural and dynamic profile as the wild-type protein and thus binds PK11195 with comparable affinity. Our study is important for the design of more potent diagnostic and therapeutic ligands of TSPO.
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany).
authors.forename: Mariusz
authors.initials: M
authors.lastname: Jaremko
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany).|German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen (Germany).
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Jaremko
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany).
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany).
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany). markus.zweckstetter@dzne.de.|German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen (Germany). markus.zweckstetter@dzne.de.|DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, 37073 Göttingen (Germany). markus.zweckstetter@dzne.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D018079:Receptors, GABA / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: C463819:Bzrp protein, mouse; D007546:Isoquinolines; D008024:Ligands; D018079:Receptors, GABA; C037850:PK 11195
keywords: NMR spectroscopy; dynamics; membrane proteins; polymorphism; protein structures