Journal
ACS CHEMICAL NEUROSCIENCE
Volume 12, Issue 9, Pages 1674-1687Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.1c00126
Keywords
Corticotropin-releasing factor receptor type 1; urocortin 1; molecular dynamics simulation; dynamical network analysis; activation mechanism
Funding
- New Jersey Health Foundation [PC 76-21]
- U.S. National Science Foundation [NSF ACI-1429467/RUI-1904797, XSEDE MCB 170088]
- Anton2 machine time at the Pittsburgh Supercomputing Center [PSCA17017P]
- National Natural Science Foundation of China [11575021, U1930402]
Ask authors/readers for more resources
This study constructed a full-length homology model of CRF1R and conducted molecular dynamics simulations of its complexes with agonist and antagonist, revealing important conformational changes in TMD and key residues. The observed dynamic rearrangements and residue interactions provide insights for ligand design targeting CRF1R activation.
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/interregional hydrogen bonds in the TMD. Dynamical network analysis identifies communities with high connections to TM6. Simulations reveal three key residues, Y356(6.53), Q384(7.49), and L395(7.60), 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available