Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms

Current Opinion in Toxicology
Laura BonatiStefano Motta

Abstract

Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR:ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.

Citations

Mar 1, 2018·PLoS Computational Biology·Stefano MottaAlessandro Pandini
Jan 10, 2020·SAR and QSAR in Environmental Research·E Goya-JorgeR Gozalbes
May 21, 2020·Journal of Clinical Medicine·Aleksandr A ArtyukovEmma P Kozlovskaya
Jul 25, 2019·Scientific Reports·Sara Giani TagliabueLaura Bonati
Sep 12, 2018·International Journal of Molecular Sciences·Samantha C FaberMichael S Denison
Jan 27, 2019·Scientific Reports·Ludovica MarinelliNicolas Lapaque
Nov 25, 2020·Molecular Biology and Evolution·Jac M M J G AartsWil Roebroeks
Mar 12, 2021·Journal of Molecular Graphics & Modelling·Mosè CasalegnoGuido Sello
Sep 25, 2020·European Journal of Medicinal Chemistry·Elizabeth Goya-JorgeRosa M Giner
Oct 9, 2021·Drug Discovery Today·Ting Xiang LimDavid C Reutens

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