Activation Mechanism of Corticotrophin Releasing Factor Receptor Type 1 Elucidated Using Molecular Dynamics Simulations

• DOI: 10.1021/acschemneuro.1c00126
• Publication Date: 2021-04-16T12:22:36Z
• Authors: Abdullahi Ibrahim...; Nicolas Scorese; Emily Dean; Haiguang Liu; Chun Wu
• Keywords: 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; Binding Sites; Adrenocorticotropic Hormone; Protein Domains; Hydrogen Bonding; Molecular Dynamics Simulation; Ligands

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 neurodisorders. However, there is no approved drug targeting the CRF1R to date, partly due to inadequate structural information and its elusive activation mechanism. Here, by use of 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 or small molecule antagonist CP-376395 were subjected to all-atom molecular dynamics simulations. We observed well preserved helical contents in the TMD through simulations, while the transmembrane (TM) helices showed clear rearrangements. The TM rearrangement is especially pronounced for the TM6 in the agonist-bound CRF1R system. The observed conformational changes are likely due to breakage of interhelical/inter-regional hydrogen bonds in the TMD. Dynamical network analysis identifies communities with high connections to TM6. Simulations reveal three key residues, Y3566.53, Q3847.49, and L3957.60, which corroborate experimental mutagenesis data, implying the important roles in the receptor activation. The observed large-scale conformational changes are related to CRF1R activation by agonist binding, providing guidance for ligand design.