The corticotropin-releasing factor receptor type 1 (CRF1R), a member of Class B G-protein-coupled receptors (GPCRs), is a good drug target for treating depression, anxiety, and other stress-related neuro-disorders. However, there is no approved drug targeting the CRF1R to date, partly due to inadequate structural information and its elusive activation mechanism. Here, using the crystal structures of its transmembrane domain (TMD) and the N-terminal extracellular domain (ECD) as a template, a full-length homology model of CRF1R was built and its complexes with peptide agonist Urocortin 1 and small molecule antagonist CP-376395 were subjected to all-atom molecular dynamics simulations. We observed relative rigid helices with helical contents well preserved through simulations, while the transmembrane helices (TMs) showed rearrangements, in particular the TM6 in the agonist-bound CRF1R. The observed conformational changes are likely due to breakage of inter-helical/inter-regional hydrogen bonds in the TMD. Dynamical network analysis identifies communities with frequent connections to TM6. Three key residues, Y3566.53, Q3847.49, and L3957.60, identified from the simulation and network analysis corroborate with experimental mutagenesis data, indicating their important roles in the activation of the receptor. The observed large-scale conformational changes and the underlying mechanism are related to CRF1R activation by agonist binding, providing guidance for ligand design.

Activation mechanism of corticotrophin releasing factor receptor Type 1 elucidated using molecular dynamics simulation

ACS Fall 2021

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