Computational prediction of the odorant receptor OR5K1 binding site structure and its interactions with pyrazine-based agonists

Thu-P1-051

Presented by: Antonella Di Pizio

Alessandro Nicoli ¹, Franziska Haag ¹, Patrick Marcinek ¹, Ruiming He ¹, Johanna Kreißl ¹, Jörg Stein ¹, Alessandro Marchetto ², Andreas Dunkel ¹, Thomas Hofmann ³, Dietmar Krautwurst ¹, Antonella Di Pizio ¹

¹ Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany, ² Institute for Advanced Simulations (IAS)-5/Institute for Neuroscience and Medicine (INM)-9, Forschungszentrum Jülich, 52428 Jülich, Germany, ³ Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354 Freising, Germany

The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists.¹ Despite the recent advancements in structural biology, no experimental structures of human odorant receptors are available. We computationally investigated the binding modes of OR5K1 ligands into the orthosteric binding site using structural information both from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from template-based modeling. Our work provides a comparison of different computational techniques for modeling odorant receptors and a model refinement protocol that succeeded to rationalize the different activity values of known OR5K1 agonists.² Moreover, by integrating modeling analyses with functional and mutagenesis experiments, we could characterize the binding site for alkylpyrazines in OR5K1, and identify residues that are necessary for receptor activation.

(1) Marcinek et al. An evolutionary conserved olfactory receptor for foodborne and semiochemical alkylpyrazines. FASEB J 2021, 35 (6), e21638.
(2) Nicoli et al. Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1. bioRxiv 2022.06.01.494157; doi: 10.1101/2022.06.01.494157