title: Conformational Flexibility in the Transmembrane Protein TSPO.
abstract: The translocator protein (TSPO) is an integral membrane protein that interacts with a wide variety of endogenous ligands, such as cholesterol and porphyrins, and is also the target for several small molecules with substantial in vivo efficacy. When complexed with the TSPO-specific radioligand (R)-PK11195, TSPO folds into a rigid five-helix bundle. However, little is known about the structure and dynamics of TSPO in the absence of high-affinity ligands. By means of NMR spectroscopy, we show that TSPO exchanges between multiple conformations in the absence of (R)-PK11195. Extensive motions on time scales from pico- to microseconds occur all along the primary sequence of the protein, leading to a loss of stable tertiary interactions and local unfolding of the helical structure in the vicinity of the ligand-binding site. The flexible nature of TSPO highlights the importance of conformational plasticity in integral membrane proteins.
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen (Germany).|German Center for Neurodegenerative Diseases (DZNE), 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, 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, 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, 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, Göttingen (Germany). Markus.Zweckstetter@dzne.de.|German Center for Neurodegenerative Diseases (DZNE), Göttingen (Germany). Markus.Zweckstetter@dzne.de.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Göttingen (Germany). Markus.Zweckstetter@dzne.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D001665:Binding Sites; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D007546:Isoquinolines; D008024:Ligands; D008565:Membrane Proteins; C037850:PK 11195
keywords: NMR spectroscopy; dynamics; function; membrane proteins; small molecules; structure