Abstract
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.
Highlights
The mTSPO_NMR model (Figure 2A) reveals some drawbacks: (i) Residues N92, W93, W95, I98, F100, G101, and A102, experimentally identified to be located at the monomer-monomer interface, are separated by a distance of 9 Å or more (Table 1 and Figure 2A); (ii) there are six residues, from F74 to M79, located at the dimer interface, that were found elsewhere experimentally (Table 1 and Figure 2A); (iii) The predicted embedding of the protein into the membrane shows that the dimer is significantly tilted with respect to the membrane plane
We underline that the embedding in the mitochondria membrane is compatible with the generalized membrane used by the Positioning of Proteins in Membranes (PPM) server
The PPM database contains the monomer of mouse translocator membrane protein (TSPO) embedded in mitochondria membrane and either the tilt and membrane thickness is fully compatible with our modeled structure (Figure 2E); (iv) Several charged residues are exposed towards the membrane; (v) PK11195 forms highly stabilizing interactions in the Bacillus cereus TSPO/PK11195 X-ray structure (PDBiD: 4RYI) (these are π-stacking interactions with F90 and hydrogen bonds (H-bonds) with W51 (Figure S2B,C)) [36], not present in this model
Summary
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