TY  - JOUR
AU  - Fierro, Fabrizio
AU  - Suku, Eda
AU  - Alfonso-Prieto, Mercedes
AU  - Giorgetti, Alejandro
AU  - Cichon, Sven
AU  - Carloni, Paolo
TI  - Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis
JO  - Frontiers in molecular biosciences
VL  - 4
SN  - 2296-889X
CY  - Lausanne
PB  - Frontiers
M1  - FZJ-2017-06445
SP  - 63
PY  - 2017
AB  - Human G-protein coupled receptors (hGPCRs) constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.
LB  - PUB:(DE-HGF)16
C6  - pmid:28932739
UR  - <Go to ISI:>//WOS:000455311400028
DO  - DOI:10.3389/fmolb.2017.00063
UR  - https://juser.fz-juelich.de/record/837557
ER  -