Unifying view of mechanical and functional hotspots across class A GPCRs.
G protein-coupled receptors (GPCRs) are the largest superfamily of signaling proteins. Their activation process is accompanied by conformational changes that have not yet been fully uncovered. Here, we carry out a novel comparative analysis of internal structural fluctuations across a variety of receptors from class A GPCRs, which currently has the richest structural coverage. We infer the local mechanical couplings underpinning the receptors' functional dynamics and finally identify those amino acids whose virtual deletion causes a significant softening of the mechanical network. The relevance of these amino acids is demonstrated by their overlap with those known to be crucial for GPCR function, based on static structural criteria. The differences with the latter set allow us to identify those sites whose functional role is more clearly detected by considering dynamical and mechanical properties. Of these sites with a genuine mechanical/dynamical character, the top ranking is amino acid 7x52, a previously unexplored, and experimentally verifiable key site for GPCR conformational response to ligand binding.
SISSA, Trieste, Italy.
Luca
0000-0001-8125-582X
L
Ponzoni
IAS-5/INM-9: Computational Biomedicine - Institute for Advanced Simulation (IAS) / Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, Jülich, Germany.|JSC: Division Computational Science - Simulation Laboratory Biology - Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, Jülich, Germany.|JARA-HPC, Jülich, Germany.|Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Giulia
G
Rossetti
IAS-5/INM-9: Computational Biomedicine - Institute for Advanced Simulation (IAS) / Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, Jülich, Germany.
Luca
L
Maggi
IAS-5/INM-9: Computational Biomedicine - Institute for Advanced Simulation (IAS) / Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, Jülich, Germany.|Department of Biotechnology, University of Verona, Verona, Italy.
Alejandro
A
Giorgetti
IAS-5/INM-9: Computational Biomedicine - Institute for Advanced Simulation (IAS) / Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, Jülich, Germany.
Paolo
P
Carloni
SISSA, Trieste, Italy.
Cristian
0000-0002-1022-1638
C
Micheletti
D001665:Binding Sites; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000648:ultrastructure*; D013329:Structure-Activity Relationship
D043562:Receptors, G-Protein-Coupled