Transmembrane (TM) proteins are essential conduits of extracellular information, regulating cell signalling. Their position at the boundary between the extracellular and intracellular environments also makes them prime targets in the early stages of host-pathogen interactions. Therefore, these membrane proteins play a key role in normal and pathological human physiology.
In this context, our research aims to characterize the molecular basis of ligand binding, activation mechanism and regulation of TM proteins using molecular pharmacology and an integrated structural biology approach combining biochemistry, NMR spectroscopy, crystallography, cryoEM, structural mass spectrometry (native and HDX) and bioinformatics. We are particularly interested in proteins with high potential for the development of therapeutic molecules, such as G protein-coupled receptors (GPCRs) and enzymes controlling ceramide homeostasis. Building on this knowledge, we use chemoinformatics approaches, and in particular AI, to identify original ligands that can modulate the activity and function of TM proteins. These ligands constitute both tools for studying the function of proteins of interest in vivo, and a starting point for the development of innovative drug discovery programs.

Structure, dynamics and molecular pharmacology of GPCR signaling complexes analyzed using a combination of Cryo electron microscopy and Lipidic cubic phase crystallography (CryoEM and LCP), Hydrogen-Deuterium exchange mass spectrometry (HDX-MS), molecular dynamics simulations (MD) and FRET- or BRET-based assays in living cells.
Team leader
DR1, Inserm

IGF Nord 204a

04 34 35 92 80
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DR2, Inserm

IGF Sud 001

04 34 35 92 68
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Researchers
PU, UM

IGF Sud 025

04 34 35 93 24
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CRCN, CNRS

IGF Nord 204b

04 34 35 92 80
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DR2, CNRS

IGF Sud 025

04 34 35 93 45
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CRCN, Inserm

IGF Nord 226

04 34 35 93 02
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CRCN, Inserm

IGF Nord 213

04 34 35 92 80
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CRHC, CNRS

IGF Nord 224

04 34 35 93 20
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PU-PH2, UM

CHU

04 34 35 92 64
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CRCN, Inserm

IGF Nord 204b

04 34 35 92 80
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Technicians and engineers
IEHC, CNRS

IGF Nord 226a

04 34 35 93 02
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Postdoctoral researchers and doctoral students
Doctorant(e), UM

IGF Nord 207c

04 34 35 92 64
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Chercheur CDD, CNRS

IGF Nord 207c

04 34 35 92 64
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Chercheur CDD, Inserm

IGF Nord 204a

04 34 35 92 80
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Fixed term contract technicians and engineers
IE CDD, Inserm

IGF Nord 204a

04 34 35 92 80
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IE CDD, Inserm

IGF Nord 207b

04 34 35 92 64
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IE CDD, Inserm

IGF Nord 207c

04 34 35 92 64
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IE CDD, CNRS

IGF Nord 209b

04 34 35 92 64
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Trainees
Master 1, UM

IGF Sud 025

04 34 35 93 24
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Master 1, CNRS

IGF Nord 204a

04 34 35 92 80
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Stagiaire, CNRS

IGF Nord 226

04 34 35 92 68
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- Bous J, Fouillen A, Orcel H, Trapani S, Cong X, Fontanel S, Saint-Paul J, Lai-Kee-Him J, Urbach S, Sibille N, Sounier R, Granier S#, Mouillac B#, Bron P#. Structure of the vasopressin hormone-V2 receptor-β-arrestin1 ternary complex. Science Adv. 2022 Sep 2;8(35):eabo7761. doi: 10.1126/sciadv.abo7761. # Co-corresponding authors.
- Healey RD, Saied EM, Cong X, Karsai G, Gabellier L, Saint Paul J, Del Nero E, Jeannot S, Drapeau M, Fontanel S, Maurel D, Basu S, Leyrat C, Golebiowski J, Bossis G, Bechara C, Hornemann T, Arenz C, Granier S. Discovery and mechanism of action of small molecule inhibitors of ceramidases. Angew Chem Int Ed Engl. 2021 Oct 20. doi: 10.1002/anie.202109967.
- Grison CM, Lambey P, Jeannot S, Del Nero E, Fontanel S, Peysson F, Heuninck J, Sounier R, Durroux T, Leyrat C, Granier S#, Bechara C#. Molecular insights into mechanisms of GPCR hijacking by Staphylococcus aureus. Proc Natl Acad Sci U S A. 2021 Oct 19;118(42):e2108856118. doi: 10.1073/pnas.2108856118. # Co-corresponding authors.
- Cong X, Maurel D, Déméné H, Vasiliauskaité-Brooks I, Hagelberger J, Peysson F, Saint-Paul J, Golebiowski J, Granier S#, Sounier R#. Molecular insights into the biased signaling mechanism of the μ-opioid receptor. Mol Cell. 2021 Oct 21;81(20):4165-4175.e6. doi: 10.1016/j.molcel.2021.07.033. Epub 2021 Aug 24. # Co-corresponding authors.
- Bous J, Orcel H, Floquet N, Leyrat C, Lai-Kee-Him J, Gaibelet G, Ancelin A, Saint-Paul J, Trapani S, Louet M, Sounier R, Déméné H, Granier S#, Bron P#, Mouillac B#. Cryo-electron microscopy structure of the antidiuretic hormone arginine-vasopressin V2 receptor signaling complex. Sci Adv. 2021 May 21;7(21). doi: 10.1126/sciadv.abg5628. # Co-corresponding authors.
- Vasiliauskaité-Brooks I, Healey RD, Rochaix P, Saint-Paul J, Sounier R, Grison C, Waltrich-Augusto T, Fortier M, Hoh F, Saied EM, Arenz C, Basu S, Leyrat C, Granier S#. Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy.Nature Commun. 2018 Dec 21;9(1):5437.
- Vasiliauskaité-Brooks I, Sounier R, Rochaix P, Bellot G, Fortier M, Hoh F, De Colibus L, Bechara C, Saied EM, Arenz C, Leyrat C#, Granier S#. Structural insights into adiponectin receptors suggest ceramidase activity. 2017 Apr 06;544:120-123. doi: 10.1038/nature21714. # Co-corresponding authors.
- Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, Kobilka BK, Déméné H, Granier S. Propagation of conformational changes during μ-opioid receptor activation. Nature. 2015 Aug 20;524(7565):375-8.
- Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK. Structure of the δ-opioid receptor bound to naltrindole. 2012 May 16;485(7398):400-4.
- Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. 2012 Mar 21;485(7398):321-6.

Molecular and structural mechanisms of GPCRs function
Principal investigators
Rémy SOUNIER, Thierry DURROUX et Christiane MENDRE
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G protein-coupled receptors and pathogens
Principal investigator
Chérine BECHARA
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Ceramide Homeostasis
Principal investigator
Xiaojing CONG
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Protein and drug design
Principal investigators
Cédric LEYRAT et Xiaojing CONG
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