Characterisation of the ligand binding sites in the translocator protein TSPO using the chimeric bacterial-mammalian constructs

Graeber, Elisabeth; Korkhov, Volodymyr M.

doi:10.1016/j.pep.2019.105456

Cited by 7 publications

(5 citation statements)

References 49 publications

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“…The high-resolution 3D structure of mTSPO either in complex with ( R ) 2 or alone was attained using solution-state NMR spectroscopy, and further insights were provided by X-ray crystallography of bacterial homologous proteins. , The RsTSPO structure at a resolution of 10 Å showed that the monomeric TSPO forms dimers in the membrane, and the monomer is composed of five TM helices. Thus, the five α-helices of the monomer are assembled into a ten-helix bundle with a 2-fold symmetry axis perpendicular to the membrane . Because of the high sequence conservation, this TSPO structure is assumed to be retained in mammalian species and bacteria.…”

Section: Studies On Tspo Structure That Followed Our Workmentioning

confidence: 69%

“…Thus, the five α-helices of the monomer are assembled into a ten-helix bundle with a 2-fold symmetry axis perpendicular to the membrane. 58 Because of the high sequence conservation, this TSPO structure is assumed to be retained in mammalian species and bacteria. Changes in the organization of the TSPO secondary structure upon ligand addition were suggested by studies based on the hydrogen/deuterium exchange of amide protons.…”

Section: Studies On Tspo Structure That Followedmentioning

confidence: 99%

“…As discussed more in detail in sections and , structural studies on TSPO have evidenced that there are different binding sites; in particular, the ligands 1b and 2 have different (but allosterically coupled) binding sites on TSPO, making the concept agonist/antagonist not fully appropriate from a structural standpoint. ,, Moreover, even from a pharmacological/functional standpoint, caution should be paid because, for example, both 1b and 2 at concentrations in the nM range appear to stimulate steroidogenesis. , Both 1b and 2 at concentrations close to their TSPO affinity are antiapoptotic and give rise to neuroprotection, even though differences in the activity elicited by the two ligands can be highlighted using different experimental conditions . Conversely, 1b showed antidepressant properties in the forced swimming test and this effect is blocked by 2 .…”

Section: Introductionmentioning

confidence: 99%

“…As discussed more in detail in sections 2.4 and 3, structural studies on TSPO have evidenced that there are different binding sites; 58 in particular, the ligands 1b and 2 have different (but allosterically coupled) binding sites on TSPO, 59 making the concept agonist/antagonist not fully appropriate from a structural standpoint. 15,60,61 Moreover, even from a pharmacological/functional standpoint, caution should be paid because, for example, both 1b and 2 at concentrations in the nM range appear to stimulate steroidogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

Giordani¹,

Menziani

Moresco

et al. 2021

J. Med. Chem.

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Translocator protein 18 kDa [TSPO or peripheraltype benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.

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Section: Studies On Tspo Structure That Followed Our Workmentioning

confidence: 69%

Section: Studies On Tspo Structure That Followedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

Giordani¹,

Menziani

Moresco

et al. 2021

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Targeted creation of IDP chimeras in vivo with similar functionality and biophysical signatures might reveal regions and distinct features that are crucial for protein function and open novel avenues for protein design. Chimeric protein approaches were successfully used for folded proteins involved in the development of multiple diseases such as breast cancer, neuroinflammation, Alzheimer's disease, or addiction [235][236][237]. Chimeras of plant and metazoan IDPs may thus reveal potential targets to improve plant growth under stress conditions or to improve our understanding of key players in human diseases.…”

Section: Methodological Advances and Outlookmentioning

confidence: 99%

Common Functions of Disordered Proteins across Evolutionary Distant Organisms

Wallmann

Kesten

2020

IJMS

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Intrinsically disordered proteins and regions typically lack a well-defined structure and thus fall outside the scope of the classic sequence-structure-function relationship. Hence, classic sequence-or structure-based bioinformatic approaches are often not well suited to identify homology or predict the function of unknown intrinsically disordered proteins. Here, we give selected examples of intrinsic disorder in plant proteins and present how protein function is shared, altered or distinct in evolutionary distant organisms. Furthermore, we explore how examining the specific role of disorder across different phyla can provide a better understanding of the common features that protein disorder contributes to the respective biological mechanism. being defined by a separate set of parameters compared to their structured and globular counterparts [7]. Hence, identification of distantly related IDPs cannot rely on structure, which can help to detect relationships of folded proteins that would remain undetected by conventional sequence-based methods [8]. Methods that use antibodies to metazoan proteins to identify putative plant homologues may result in a higher incidence of artefacts when compared to folded protein targets, due to the smaller size of disordered epitopes and their comparably higher sensitivity to epitope variation [9].In contrast to folded proteins, IDPs and IDRs show an overall increased rate of evolution, while these rates can strongly vary between different parts of the IDP [10,11]. Moreover, disordered regions appear to be more permissive to mutation, further complicating sequence-function analysis. Overall, genome duplication events seem to influence the distribution of IDRs within genomes, as the amount of identical paralogous IDRs positively correlates with the number of chromosomes [12]. Interestingly, proteins can display different modes of how sequence conservation can relate to disorder as a functional feature [13]. While in some cases only the disorder itself is conserved, but not the sequence facilitating it (flexible disorder), other IDPs retain disorder together with a highly conserved sequence (constrained disorder). Short-linear motifs (SLiMs) represent conserved functional modules that can mediate low-affinity interactions and are often interspersed by regions of flexible disorder [14]. As many alignment algorithms require long stretches of sequence similarity to satisfy statistical significance, the high modality and low complexity of SLiMs can obscure the search for homologous sequences considerably. Due to their limited size (7-12 residues), these motifs can easily develop in unrelated proteins in convergent evolution. Furthermore, post-translational modifications (PTMs) that often regulate IDP function complicate the analysis, as they can drastically alter the biophysical features of a protein and phosphorylation sites display short and weakly conserved motifs that are often difficult to detect via computational sequence analysis [15].Within protein interaction networks, IDPs ofte...

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18-kDa translocator protein association complexes in the brain: From structure to function

Costa

Pozzo

Martini

2020

Biochemical Pharmacology

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Characterisation of the ligand binding sites in the translocator protein TSPO using the chimeric bacterial-mammalian constructs

Cited by 7 publications

References 49 publications

Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria

Common Functions of Disordered Proteins across Evolutionary Distant Organisms

18-kDa translocator protein association complexes in the brain: From structure to function

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