The mutual and dynamic role of TSPO and ligands in their binding process: An example with PK-11195

Translocator protein (TSPO) is an 18 kDa transmembrane protein, localized primarily on the outer mitochondrial membrane. It has been found to be involved in various physiological processes and pathophysiological conditions. Though studies on its structure have been performed only recently, there is...

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Bibliographic Details
Published in:	Biochimie Vol. 224; pp. 29 - 40
Main Authors:	Rao, Rajas M., El Dhaybi, Ibaa, Cadet, Frédéric, Etchebest, Catherine, Diharce, Julien
Format:	Journal Article
Language:	English
Published:	France Elsevier B.V 01-09-2024
Subjects:	Animals Binding Sites Conformational analysis Conformational space Isoquinolines - chemistry Isoquinolines - metabolism Ligand-receptor interaction Ligands Mice Molecular dynamics Molecular Dynamics Simulation Protein Binding Receptors, GABA - chemistry Receptors, GABA - metabolism TSPO Molecular dynamics TSPO Conformational space Ligand-receptor interaction Conformational analysis
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Summary:	Translocator protein (TSPO) is an 18 kDa transmembrane protein, localized primarily on the outer mitochondrial membrane. It has been found to be involved in various physiological processes and pathophysiological conditions. Though studies on its structure have been performed only recently, there is little information on the nature of dynamics and doubts about some structures referenced in the literature, especially the NMR structure of mouse TSPO. In the present work, we thoroughly study the dynamics of mouse TSPO protein by means of atomistic molecular dynamics simulations, in presence as well as in absence of the diagnostic ligand PKA. We considered two starting structures: the NMR structure and a homology model (HM) generated on the basis of X-ray structures from bacterial TSPO. We examine the conformational landscape in both the modes for both starting points, in presence and absence of the ligand, in order to measure its impact for both structures. The analysis highlights high flexibility of the protein globally, but NMR simulations show a surprisingly flexibility even in the presence of the ligand. Interestingly, this is not the case for HM calculations, to the point that the ligand seems not so stable as in the NMR system and an unbinding event process is partially sampled. All those results tend to show that the NMR structure of mTSPO seems not deficient but is just in another portion of the global conformation space of TSPO. •Mouse TSPO is a highly dynamic structure.•Despite similar helical contents, conformations show various side chain TM contacts.•TSPO remains highly flexible even bound to the PK-11195 ligand.•Both TSPO and ligands are mutually adaptative to each other for efficient binding.•This mutual adaptation is totally relevant with the diversity of TSPO ligands.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0300-9084 1638-6183 1638-6183
DOI:	10.1016/j.biochi.2024.03.009