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Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / NURY Hugues

Nury & Pebay-Peyroula team

Presentation

Our research aims to better understand how membrane machines operate at the molecular scale, using structural biology. We mainly work with pentameric neurotransmitter-gated channels, and with the phosphate transporter of Toxoplasma gondii.
Our projects mix state-of-the-art eukaryotic expression systems, solid biochemistry, biophysical characterization, electrophysiology, and two structural methods: X-ray crystallography and cryo-EM.
Our research is curiosity-driven, but focuses on membrane proteins that play crucial roles in health and disease.

Pentameric ligand-gated ion channels (pLGICs)

In the nervous system, pLGICs mediate fast neurotransmission. They function as allosteric signal transducers across the plasma membrane: upon binding neurotransmitter molecules, they undergo complex conformational transitions that result in transient openings of an intrinsic ion channel. The family comprises receptors activated by glycine, GABA, acetylcholine and serotonin. We aim to reveal the operation mechanism(s) of pLGICs, to decipher their conformational transitions, to understand their pharmacology. We have obtained results mostly with the serotonin 5-HT3 receptor.
In the recent years, we obtained a X-ray structure of the 5-HT3 receptor in complex with inhibitory nanobodies (Hassaine et al, Nature 2014) and several cryo-EM structures of the same receptor in different conformations (Polovinkin et al., Nature 2018) stabilized by small molecules (agonists, clinical antagonists, modulators, …).

PNG

Collaborations :
Francois Dehez et Chris Chipot (LIA, Nancy)
Ghérici Hassaine (Theranyx, Marseille)
Anders Jensen (Department of drug design and pharmacology, University of Copenhagen, Copenhague)

Funding
CNRS, CEA, UGA, Marie Curie actions (CIG 631416), ERC (Starting Grant PentaBrain), FRM

APT, the Apicoplast Phosphate Transporter from T.gondii , E.Pebay-Peyroula

Plasmodium and Toxoplasma gondii are obligate intracellular parasites that harbor a plastid, the apicoplast, which is responsible for vital functions such as fatty acid synthesis and isoprenoid synthesis. The import of the essential substrates for these pathways have been shown to be relying on the sole characterized transporter of the apicoplast of T. gondii and Plasmodium: APT. APT belongs to the family of triosephosphate/phosphate transporters found in plant chloroplasts. It was shown that the disruption of the APT gene in T. gondii leads to immediate death of the parasite. Our project aims at solving the structure of APT, at atomic resolution by X-ray crystallography. Since 2015, we set-up production protocols and characterization technics (thermal stability, transport properties,...). More recently, we exploit nanobodies to stabilize single conformations and enhance the chances to get crystals.

Collaborations:
K. Fischer (AMB, UiT Tromsø)
C. Botté (IAB, UGA Grenoble)
H. Hassanzadeh (VIB, Brussels)

High throughput in meso membrane protein crystallization platform, F. Dupeux

The team includes the lipidic cubic phase crystallization platform (HTMPC).

Major past achievements

Bacterial rhodopsins (1994-2004), E. Pebay-Peyroula
- First structure of a membrane protein crystallized in lipidic cubic phases
Pebay-Peyroula et al. Science 1997; Belrhali et al. Structure 1999
- Structures of sensory rhodopsin II and intermediate states of bacteriorhodopsin
Edman et al. Nature 1999; Royant et al. Nature 2000; Royant et al. PNAS 2001
- Main collaborations: J. Rosenbusch, E. Landau and R. Neutze.

The mitochondrial ADP/ATP carrier (2000-2017), E.Pebay-Peyroula and S.Ravaud

From 2000 to 2017 we investigated the transport of nucleotides in mitochondria and also in chloroplasts and obligate intracellular bacteria. In 2003, we solved the first structure of the mitochondrial ADP/ATP carrier (AAC), a MCF member (Mitochondrial carrier family) (Pebay-Peyroula et al. Nature 2003). Theoretical calculations showed the importance of electrostatics in attracting nucleotides to their binding site (Dehez et al. JACS 2008). Activity measurements combined synergistically with molecular-dynamics simulations demonstrate how all documented pathological mutations alter the binding affinity and the translocation kinetics of the nucleotides (Ravaud et al. ACS ChemBio 2003). We also studied another family of nucleotide transporters (NTTs) from chloroplasts and intracellular pathogenic bacteria. Their mechanism of action is probably different as they exchange ATP against ADP and Pi, and are predicted to bare 12 transmembrane helices. We developed production, purification and characterization protocols.
Main collaborations: B. Miroux, M. le Maire, C. Chipot and F. Dehez.

Ph.D. theses

A list of Ph.Ds. in the group can be found here.

Key publications

The complete list of our publications is available here.

Team members

Céline Juillan-Binard (Research technican CEA)
Delphine Baud (Research technican CEA)
Eva Pebay-Peyroula (Professor UGA)
Florine Dupeux (Research engineer CNRS)
Hugues Nury (Scientist CNRS)
Jacques Neyton (Scientist CNRS)
Jonathan Perot (Research engineer CNRS)
Lefteris Zarkadas (Postdoc CNRS)
Lucie Polovinkin (PhD student)
Uriel Lopez-Sanchez (Postdoc UGA/FRM)

Alumni
Sonja Minniberger (never-ending Master student, 2014-2015), now PhD student in the Plested lab in Berlin
Orso Subrini (Postdoc 2015-2017, now at micro-pep.com)

Work with us

If you are interested in our research, get in contact with Hugues or Eva. Applications from scientists who like their job with passion and do it with rigour, at any career stage, will be considered with care.
hugues[dot]nury[at]ibs[dot]fr
eva[dot]pebay-peyroula[at]ibs[dot]fr