Stability and activation of G-protein-coupled receptors
|Research Area||Bio Sciences|
|Principal Investigator(s)||PhD DSc Slawomir Filipek|
Plasticity of GPCR is essential for their function since different ligands invoke different rearrangements of receptor structure (for full and partial agonists and also inverse agonists) enabling to signal different processes via stimulatory or inhibitory G-protein or via arrestin. Because there are about 800 types of GPCRs and only a dozen of G proteins and three arrestins there are similarities in activation processes of GPCRs. These processes are ruled by molecular switches: breaking of hydrogen bond or electrostatic interaction or even conformational change of amino acid residue. Some of these switches are interdependent or time dependent and different ligands can activate specific sets of switches. In this project some of these receptors will be investigated in complexes with agonists up to microsecond time scale to investigate action of molecular switches concurrent with ligand binding. Because most of GPCRs apart from binding diverse ligands are active even without a ligand bound they must exist in different conformations in room temperature with a dynamical balance between them. This raises a question about a stability of GPCRs in the membrane. The nature and location of structural segments responsible for stability can be revealed by unfolding the receptor by pulling it from the membrane. Experimental data from SMFS (Single Molecule Force Spectroscopy) are available for rhodopsin and we plan to simulate unfolding path of rhodopsin to get direct insight what is going on the molecular level during this process and unveil particular roles and interdependence of stable structural segments.