Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1
Alessandro Nicoli, Franziska Haag, Patrick Marcinek, Ruiming He, Johanna Kreißl, Jörg Stein, Alessandro Marchetto, Andreas Dunkel, Thomas Hofmann, Dietmar Krautwurst, Antonella Di Pizio
Abstract
. Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Mutagenesis data guided side chain residue sampling and model selection. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models and also capture differences in activity related to minor structural differences. Therefore, we provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates.