Deepen cytokine / receptor interaction by in silico Studies.
Cytokine / Receptor interactions study
Comparison of the binding of IL-2, IL-4 and IL-15 to the γc chain.
Details of interactions between interleukin-15 (IL-15) and IL-15 Receptor α (IL-15Rα). Two salt-bridges by E53 and E46 of IL-15 and R26 and R35 of IL-15Rα, respectively, contribute substantiallyto the high affinity of the IL-15/IL-15Rα interaction.
Details of interactions between IL-34 and CSF-1 Receptor.
Molecular modeling and protein-protein docking
to
- provide structural models for proteins without available PDB structure
- model fusion proteins
- provide structural model of protein-protein complex interface
Cases studies
Models of IL-15, the sushi domain of IL-15Rα and the IL-15/IL-15Rα complex. The models (representation in ribbon or with the colored Connolly surface with a hydrophobicity index of (A) IL-15 and (B) IL-15Rα were obtained by homology modeling. (C) IL-15/IL-15Rα complex models were obtained using protein-protein docking programs.
Structural model of an IL-15-based fusion protein, named RLI
Development of a RLI-based immunocytokine (ICK) targeting the tumor-associated antigen GD2. (A) The C-terminus of the heavy chain of an anti-GD2 antibody was fused to the N-terminus of RLI. (B) The anti-GD2-RLI ICK not only efficiently bound to GD2 and IL-15 dimeric receptor IL-2Rb/gc , but also conserved both the cytotoxic effector functions of the antibody and the biological activity of the cytokine.
Structure-based virtual screening
to discover new hits for biological targets.
This activity is part of the regional project named PIRAMID and supported by la Région Pays de la Loire (http://piramid-research.fr), whose objective is the rational development of inhibitors of protein-protein interactions.
Cases studies
Discovery of small-molecule inhibitors impeding IL-15/IL-15R interaction. Pharmacophore and docking-based virtual screening of a large compound library led to the selection of one hit able to bind IL-15 and to inhibit in vitro functional effects. Its optimization by structure-activity relationship approach led to the discovery of the first small-molecule IL-15 inhibitor with sub-micromolar activity.
Selected Publications:
- Quéméner A., et al., (2019) J. Cell. Sci. 133(5):jcs236802.
- Quéménér A., et al., (2017) J. Med. Chem. 60:6249.
- Vincent M., et al., (2013) Int. J. Cancer 133:757.
- Vincent M., et al., (2013) Oncoimmunology 2:e26441.
- Bouchaud G., et al., (2008) J. Mol. Biol. 382:1.
- Mortier E., et al., (2006) J. Biol. Chem. 281:1612.
- Quéméner A., et al., (2006) Proteins 65:623.
Other Applications
Structural model 4-1BBLigand obtained by homology modeling. (A) Ribbon representation, with Connolly surface colored according to (B) a hydrophobicity index or (C) elelectrostatic potential.
Rabu C., et al., (2005) J. Biol. Chem. 280 :41472
Structures of Ras protein superfamily. (A) The Ras 3-dimensional structure is composed by 6-sheets and 5-helices. Conserved sequence motifs (G1-G5) involved in nucleotide binding are represented. (B) Similar resepresentation of Rho, Rab, Are, and Ran protein structure.
Loirand G., et al., (2013) Physiol. Rev. Biol. 93:1659.
Structural model of the protein CVP60 of European Brown Hare Syndrome Virus capsid obtained by homology modeling. P and S domains of the VP60 of the EBHSV capsid showing specific residues implicated in the epitopes of indicated mAbs.
Lopes A., et al., (2014) Virology. 468-470:104.
Identification of two novel variants in GP9 associated with Bernard-Soulier syndrome.
Boisseau P., et al., (2018) Platelets. 29:316.