Structural Prediction of the Dimeric Form of the Mammalian Translocator Membrane Protein TSPO: A Key Target for Brain Diagnostics

Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers-the suggested functional...

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Bibliographic Details
Published in:International journal of molecular sciences 2018-08, Vol.19 (9), p.2588
Main Authors: Zeng, Juan, Guareschi, Riccardo, Damre, Mangesh, Cao, Ruyin, Kless, Achim, Neumaier, Bernd, Bauer, Andreas, Giorgetti, Alejandro, Carloni, Paolo, Rossetti, Giulia
Format: Article
Language:English
Subjects:
Animals
Binding Sites
brain inflammation
Chemistry
Cholesterol - chemistry
Cholesterol - metabolism
Computational neuroscience
Detergents
docking
Homology
homology modeling
Inflammation
Laboratories
Ligands
Mammals
Membrane proteins
Mitochondria
Molecular Docking Simulation
molecular dynamics
Molecular structure
Neurological diseases
Neurosciences
NMR
Nuclear magnetic resonance
oligomerization
PET
Positron emission
Positron emission tomography
Positron-Emission Tomography - methods
Protein Binding
Protein Multimerization
Proteins
Radioisotopes
radioligands
Receptors, GABA - chemistry
Receptors, GABA - metabolism
Solid state
Tomography
Traumatic brain injury
TSPO
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Summary:Positron emission tomography (PET) radioligands targeting the human translocator membrane protein (TSPO) are broadly used for the investigations of neuroinflammatory conditions associated with neurological disorders. Structural information on the mammalian protein homodimers-the suggested functional state of the protein-is limited to a solid-state nuclear magnetic resonance (NMR) study and to a model based on the previously-deposited solution NMR structure of the monomeric mouse protein. Computational studies performed here suggest that the NMR-solved structure in the presence of detergents is not prone to dimer formation and is furthermore unstable in its native membrane environment. We, therefore, propose a new model of the functionally-relevant dimeric form of the mouse protein, based on a prokaryotic homologue. The model, fully consistent with solid-state NMR data, is very different from the previous predictions. Hence, it provides, for the first time, structural insights into this pharmaceutically-important target which are fully consistent with experimental data.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms19092588