identification and characterization of Interfering peptide to inhibit oligomerization of membrane receptor

Type de poste
Niveau d'étude minimal
Dates
Durée du poste
Contrat renouvelable
Contrat non renouvelable
Date de prise de fonction
Date de fin de validité de l'annonce
Localisation
Adresse

Campus Moulin de la Housse
BP 1039
51687 Reims 2
France

Contacts
Dr Marc Guéroult
Email du/des contacts
marc.gueroult@univ-reims.fr
Description

Some membrane receptors transduce a signal from the extracellular medium and can play an important role in many pathologies. They are therefore prime targets in the development of therapeutic molecules. These receptors may need to oligomerize to become active and transduce a signal via a signaling cascade.
As part of this internship, we will study the transmembrane domain of neuraminidase I (Neu-1). Neu-1 is part of a macrocomplex : the elastin receptor complex (ERC). The ERC consists of three partners which are: protectice protein / cathepsin A (PPCA), elastin binding protein (EBP) and Neu-1. This macro-complex is sensitive to the degradation of the extracellular matrix and more specifically to the degradation of its major constituent elastin. In a pathological context, the extracellular matrix is degraded more significantly which is felt by the cell via the ERC complex. Thus ERC and more particularly Neu-1 is a good therapeutic target and its inhibition will reduce the effect of the pathological degradation of the extracellular matrix. It is proposed using molecular modeling methods to develop an interfering peptide to inhibit the oligomerization of the Neu-1 subunit of the ERC macro-complex(1).
Simulations of molecular dynamics will be conducted on the different transmembrane domains to characterize their organizations and their orientations in the lipid bilayer which will used as a model to represent the biological membrane. From these datas, we will identify and quantify the residues involved in the formation and stability of the dimer. Based on this study, an energy decomposition (MM / PBSA) of the contribution of each of amino acids will be conducted, allowing us to identify residues that may be the target of saturating mutagenesis. The peptides thus obtained will then be tested by in silico approaches, using coarse grain methods(2) to accelerate the speed especially as the simulations will be conducted on the regional calculator (ROMEO). In parallel, a peptide-based approach to peptide design can be developed. It will also be possible to use a computational protein design approach that allows a systematic exploration of the entire combinatorics in the sequence space(3).Once the most refined sequences selected and validated by in silico approaches, this one will be tested experimentally to evaluate their capacity to inhibit the oligomerization of the dimer.

1. Maurice, P., Baud, S., Bocharova, O. V., Bocharov, E. V., Kuznetsov, A. S., Kawecki, C., ... & Duca, L. (2016). New insights into molecular organization of human neuraminidase-1: transmembrane topology and dimerization ability. Scientific reports, 6, 38363.

2. Wassenaar, T. A., Pluhackova, K., Moussatova, A., Sengupta, D., Marrink, S. J., Tieleman, D. P., & Böckmann, R. A. (2015). High-throughput simulations of dimer and trimer assembly of membrane proteins. The DAFT approach. Journal of chemical theory and computation, 11(5), 2278-2291.

3.Viricel, C., de Givry, S., Schiex, T., & Barbe, S. (2018). Cost function network-based design of protein–protein interactions: predicting changes in binding affinity. Bioinformatics, 34(15), 2581-2589.

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