Insight into the Structural Features of TSPO: Implications for Drug Development

Overview

Journal Trends Pharmacol Sci

Specialty Pharmacology

Date 2019 Dec 23

PMID 31864680

Citations 9

Authors

Jean-Jacques Lacapere

Luminita Duma

Stephanie Finet

Michael Kassiou

Vassilios Papadopoulos

Affiliations

Soon will be listed here.

Abstract

The translocator protein (TSPO), an 18-kDa transmembrane protein primarily found in the outer mitochondrial membrane, is evolutionarily conserved and widely distributed across species. In mammals, TSPO has been described as a key member of a multiprotein complex involved in many putative functions and, over the years, several classes of ligand have been developed to modulate these functions. In this review, we consider the currently available atomic structures of mouse and bacterial TSPO and propose a rationale for the development of new ligands for the protein. We provide a review of TSPO monomeric and oligomeric states and their conformational flexibility, together with ligand-binding site and interaction mechanisms. These data are expected to help considerably the development of high-affinity ligands for TSPO-based therapies or diagnostics.

Citing Articles

PK 11195 derivatives: exploring the influence of amide and heterocyclic substitution on A147T TSPO discrimination.

Sokias R, Zhao A, Werry E, Montgomery A, Hibbs D, Sullivan M RSC Med Chem. 2025; .

PMID: 40060999 PMC: 11883422. DOI: 10.1039/d4md00798k.

Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway.

Li B, Yu K, Zhou X, Sun J, Qi L, Li W J Headache Pain. 2025; 26(1):16.

PMID: 39871133 PMC: 11771075. DOI: 10.1186/s10194-025-01953-0.

Translocator Protein 18 kDa (TSPO): A Promising Molecular Target for Image-Guided Surgery of Solid Cancers.

Wongso H, Kurniawan A, Setiadi Y, Kusumaningrum C, Widyasari E, Wibawa T Adv Pharm Bull. 2024; 14(1):86-104.

PMID: 38585455 PMC: 10997928. DOI: 10.34172/apb.2024.015.

Functional role of translocator protein and its ligands in ocular diseases (Review).

Yu M, Zhao S Mol Med Rep. 2024; 29(2).

PMID: 38186312 PMC: 10804439. DOI: 10.3892/mmr.2024.13157.

Neurosteroids (allopregnanolone) and alcohol use disorder: From mechanisms to potential pharmacotherapy.

Gatta E, Camussi D, Auta J, Guidotti A, Pandey S Pharmacol Ther. 2022; 240:108299.

PMID: 36323379 PMC: 9810076. DOI: 10.1016/j.pharmthera.2022.108299.

References

Palamini M, Canciani A, Forneris F . Identifying and Visualizing Macromolecular Flexibility in Structural Biology. Front Mol Biosci. 2016; 3:47. PMC: 5016524. DOI: 10.3389/fmolb.2016.00047. View

Zeng J, Guareschi R, Damre M, Cao R, Kless A, Neumaier B . Structural Prediction of the Dimeric Form of the Mammalian Translocator Membrane Protein TSPO: A Key Target for Brain Diagnostics. Int J Mol Sci. 2018; 19(9). PMC: 6165245. DOI: 10.3390/ijms19092588. View

Jamin N, Neumann J, Ostuni M, Vu T, Yao Z, Murail S . Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor. Mol Endocrinol. 2004; 19(3):588-94. DOI: 10.1210/me.2004-0308. View

Zanotti-Fregonara P, Zhang Y, Jenko K, Gladding R, Zoghbi S, Fujita M . Synthesis and evaluation of translocator 18 kDa protein (TSPO) positron emission tomography (PET) radioligands with low binding sensitivity to human single nucleotide polymorphism rs6971. ACS Chem Neurosci. 2014; 5(10):963-71. PMC: 4210126. DOI: 10.1021/cn500138n. View

Elkamhawy A, Park J, Hassan A, Pae A, Lee J, Park B . Design, synthesis, biological evaluation and molecular modelling of 2-(2-aryloxyphenyl)-1,4-dihydroisoquinolin-3(2H)-ones: A novel class of TSPO ligands modulating amyloid-β-induced mPTP opening. Eur J Pharm Sci. 2017; 104:366-381. DOI: 10.1016/j.ejps.2017.04.015. View

Batoko H, Veljanovski V, Jurkiewicz P . Enigmatic Translocator protein (TSPO) and cellular stress regulation. Trends Biochem Sci. 2015; 40(9):497-503. DOI: 10.1016/j.tibs.2015.07.001. View

Gerber D, Sal-Man N, Shai Y . Two motifs within a transmembrane domain, one for homodimerization and the other for heterodimerization. J Biol Chem. 2004; 279(20):21177-82. DOI: 10.1074/jbc.M400847200. View

Rupprecht R, Papadopoulos V, Rammes G, Baghai T, Fan J, Akula N . Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010; 9(12):971-88. DOI: 10.1038/nrd3295. View

Dupont A, Largeau B, Santiago Ribeiro M, Guilloteau D, Tronel C, Arlicot N . Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases. Int J Mol Sci. 2017; 18(4). PMC: 5412369. DOI: 10.3390/ijms18040785. View

10.

Xia Y, Ledwitch K, Kuenze G, Duran A, Li J, Sanders C . A unified structural model of the mammalian translocator protein (TSPO). J Biomol NMR. 2019; 73(6-7):347-364. PMC: 8006375. DOI: 10.1007/s10858-019-00257-1. View

11.

Cumming P, Burgher B, Patkar O, Breakspear M, Vasdev N, Thomas P . Sifting through the surfeit of neuroinflammation tracers. J Cereb Blood Flow Metab. 2017; 38(2):204-224. PMC: 5951023. DOI: 10.1177/0271678X17748786. View

12.

Fan J, Lindemann P, Feuilloley M, Papadopoulos V . Structural and functional evolution of the translocator protein (18 kDa). Curr Mol Med. 2012; 12(4):369-86. DOI: 10.2174/1566524011207040369. View

13.

Papadopoulos V, Liu J, Culty M . Is there a mitochondrial signaling complex facilitating cholesterol import?. Mol Cell Endocrinol. 2007; 265-266:59-64. DOI: 10.1016/j.mce.2006.12.004. View

14.

Narayanaswami V, Dahl K, Bernard-Gauthier V, Josephson L, Cumming P, Vasdev N . Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO. Mol Imaging. 2018; 17:1536012118792317. PMC: 6134492. DOI: 10.1177/1536012118792317. View

15.

Kalina T, Berroteran-Infante N, Schmitl S, Vraka C, Hacker M, Mitterhauser M . Synthesis and in vitro evaluation of new translocator protein ligands designed for positron emission tomography. Future Med Chem. 2019; 11(6):539-550. DOI: 10.4155/fmc-2018-0444. View

16.

Chipot C, Dehez F, Schnell J, Zitzmann N, Pebay-Peyroula E, Catoire L . Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies. Chem Rev. 2018; 118(7):3559-3607. PMC: 5896743. DOI: 10.1021/acs.chemrev.7b00570. View

17.

Kleiger G, Grothe R, Mallick P, Eisenberg D . GXXXG and AXXXA: common alpha-helical interaction motifs in proteins, particularly in extremophiles. Biochemistry. 2002; 41(19):5990-7. DOI: 10.1021/bi0200763. View

18.

Patching S . Surface plasmon resonance spectroscopy for characterisation of membrane protein-ligand interactions and its potential for drug discovery. Biochim Biophys Acta. 2013; 1838(1 Pt A):43-55. DOI: 10.1016/j.bbamem.2013.04.028. View

19.

Owen D, Fan J, Campioli E, Venugopal S, Midzak A, Daly E . mutations in rats and a human polymorphism impair the rate of steroid synthesis. Biochem J. 2017; 474(23):3985-3999. PMC: 5697202. DOI: 10.1042/BCJ20170648. View

20.

Deeva O, Pantileev A, Rybina I, Yarkova M, Gudasheva T, Seredenin S . A Novel Dipeptide Ligand of TSPO. Dokl Biochem Biophys. 2019; 484(1):17-20. DOI: 10.1134/S1607672919010046. View