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

Abdullahi Ibrahim Uba1, Nicolas Scorese2, Emily Dean2

  • 1Complex Systems Division, Beijing Computational Science Research Center, Beijing 100193, China.

ACS Chemical Neuroscience
|April 16, 2021
PubMed

Insights

Researchers modeled the corticotropin-releasing factor receptor type 1 (CRF1R) to understand its activation mechanism. Molecular dynamics simulations revealed key conformational changes and residues crucial for CRF1R function, guiding new drug development for stress disorders.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Computational Biology

Background:

  • The corticotropin-releasing factor receptor type 1 (CRF1R) is a class B G-protein-coupled receptor (GPCR) targeted for treating depression, anxiety, and stress-related disorders.
  • Current limitations in drug development for CRF1R stem from insufficient structural data and an unclear activation mechanism.

Purpose of the Study:

  • To elucidate the activation mechanism of CRF1R by constructing a full-length homology model.
  • To investigate the conformational dynamics of CRF1R upon binding with an agonist (urocortin 1) and an antagonist (CP-376395) using molecular dynamics simulations.

Main Methods:

  • Homology modeling of the full-length CRF1R using crystal structures of its transmembrane (TMD) and extracellular domains (ECD).
  • All-atom molecular dynamics simulations of CRF1R complexes with urocortin 1 and CP-376395.
  • Dynamical network analysis to identify key residues and communities involved in receptor activation.

Main Results:

  • Transmembrane domain (TMD) helical structures remained stable, but transmembrane (TM) helices underwent significant rearrangements, particularly TM6 in the agonist-bound state.
  • Conformational changes were attributed to the disruption of interhelical hydrogen bonds within the TMD.
  • Identified three critical residues (Y356, Q384, L395) involved in receptor activation, consistent with experimental mutagenesis data.

Conclusions:

  • Agonist binding induces large-scale conformational changes in CRF1R, providing insights into its activation mechanism.
  • The identified key residues and observed dynamics offer valuable guidance for the rational design of novel CRF1R-targeting ligands.
  • Understanding CRF1R dynamics is crucial for developing effective therapeutics for stress-related neuropsychiatric disorders.
Keywords:
Corticotropin-releasing factor receptor type 1activation mechanismdynamical network analysismolecular dynamics simulationurocortin 1

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