Section: Application Domains

G-protein Coupled Receptors

Participants : Bernard Maigret [contact person] , David Ritchie, Vincent Leroux.

G-protein coupled receptors (GPCRs) are cell surface proteins which detect chemical signals outside a cell and which transform these signals into a cascade of cellular changes. Historically, the most well documented signaling cascade is the one driven by G-proteins trimers (guanine nucleotide binding proteins) [43] which ultimately regulate many cellular processes such as transcription, enzyme activity, and homeostatis, for example. But other pathways have recently been associated with the signals triggered by GPCRs, involving other proteins such as arrestins and kinases which drive other important cellular activities. For example, $\beta$-arrestin activation can block GPCR-mediated apoptosis (cell death). Malfunctions in such processes are related to diseases such as diabetes, neurological disorders, cardiovascular disease, and cancer. Thus, GPCRs are one of the main protein families targeted by therapeutic drugs [38] and the focus of much bio-medical research. Indeed, approximately 40–50% of current therapeutic molecules target GPCRs. However, despite enormous efforts, the main difficulty here is the lack of experimentally solved 3D structures for most GPCRs. Hence, computational modeling tools are widely recognized as necessary to help understand GPCR functioning and thus biomedical innovation and drug design.

In collaboration with the BIOS team (INRA Tours) and the AMIB team (Inria Saclay – Île de France) we used our Hex protein docking software to help model a multi-component G-protein coupled receptor (GPCR) complex [35]. The resulting 3D structure was shown to be consistent with the known experimental data for the protein components of this trans-membrane molecular signaling system. As part of an on-going collaboration with the Centre for Interdisciplinary Research (CIRB) at Collège de France, we modeled the interaction between the Apelin peptide and a GPCR called ApelinR [42]. This study provided mechanistic insights which could lead to the development of therapeutic agents for the treatment of heart failure.