PHD position: Deciphering mechanism activity of potent biased agonists active in nephrogenic insipidus disease
We are seeking for a higly motivated candidate to postulate for a PhD position funded by the FRM through the "Fondation Line POMARET-DELALANDE, thesis funding on rare diseases".
Thesis topic: Deciphering mechanism activity of potent biased agonists active in nephrogenic insipidus disease.
G-protein Coupled Receptors (GPCRs) represent the largest class of eukaryotic cell surface receptors involved in signal transduction. The V2 vasopressin receptor (V2R) is a prototypal receptor for peptides, which governs water homeostasis in the body. Mutations of V2R are responsible for a rare genetic disease, the congenital Nephrogenic Diabetes Insipidus (cNDI), characterized by excessive urine voiding, dehydration, hypernatremia. We have characterized the very first biased ligands of V2R that rescue with long lasting effects V2R mutants responsible for NDI (Jean-Alfonse et al., J Am Soc Nephr 2009; Rahmeh et al., Proc Natl Acad Sci USA 2012).
The thesis aims at structurally characterize the mode of action of biased ligands versus non-biased ligands using liquid NMR as principal tool (Sounier et al. 2015). The PhD student will be involved in the preparative biochemistry of V2R and NMR experiments design, recording and analysis. The results that will be generated from this work will pave the way to the design of more specific V2R ligands targeting NDI with fewer side effects and longer efficacy.
The thesis work will be carried out in close collaboration between the two groups involved: Hélène Déméné, Centre de Biochime Structurale and Bernard Mouillac, Institut de Génomique Fonctionnelle, both in Montpellier (South of France). Both groups develop transverse unique cutting-edge methodologies (biophysics, pharmacology, biochemistry, molecular simulations) to decipher the structural bases of GPCR signaling.
Selection criteria: Master students with a background in structural biology, especially in NMR, are encouraged to apply before July,12th 2018. The "Prix de Thèse sur les Maladies Rares" funded by Fondation Pomaret-Delalande-FRM is described here (dead line: August the 2nd, 2018)
Net salary/month : 1400 euros, for three years.
Sounier R, Mas C, Steyaert J, Laeremans T Manglik A, Huang W, Kobilka BK, Déméné H*, Granier S (2015)(*co-corresp author) Nature 524(7565):375-8 285(9): 6337-47.
Rahmeh R, Damian M, Cottet M, Orcel H, Mendre C, Durroux T, Sharma KS, Durand G, Pucci B, Trinquet E, Zwier JM, Deupi X, Bron P, Banères JL, Mouillac* B, Granier S (2012) (*co-corresp author) Proc Natl Acad Sci USA 109(17): 6733-38.
Jean-Alphonse F, Perkovska S, Frantz MC, Durroux T, Méjean C, Morin D, Loison S, Bonnet D, Hibert M, Mouillac B, Mendre C. (2009) J Am Soc Nephrol. 20(10):2190-203.