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Modeling TSH Receptor Dimerization at the Transmembrane Domain.

Mihaly Mezei1, Rauf Latif2,3, Terry F Davies2,3

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Molecular dynamics simulations reveal that the thyrotropin (TSH) receptor transmembrane domain (TSHR-TMD) forms stable dimers. These dimeric structures exhibit conformational changes that impact small-molecule binding affinities.

Keywords:
DPPCGPCRTSHRdimerizationdockingmolecular dynamics

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Area of Science:

  • Biophysics
  • Molecular Biology
  • Computational Chemistry

Background:

  • Biophysical studies indicate the thyrotropin (TSH) receptor (TSHR) undergoes dimerization as a posttranslational modification.
  • Previous work involved simulating a monomeric TSHR-transmembrane domain (TSHR-TMD).

Purpose of the Study:

  • To perform molecular dynamics (MD) simulations of TSHR-TMD dimerization.
  • To investigate the stability and conformational dynamics of TSHR-TMD dimers.
  • To analyze the impact of dimerization on ligand-binding sites.

Main Methods:

  • Utilized an improved, membrane-embedded model of TSHR-TMD.
  • Embedded the model in a DPPC lipid bilayer with water and salt.
  • Conducted 1000 ns of molecular dynamics (MD) simulation.
  • Compared monomeric and dimeric conformations using backbone root mean square deviations.
  • Performed docking simulations of 46 small-molecule ligands.

Main Results:

  • Dimeric TSHR-TMD subunits maintained stable relative orientation and distance throughout the simulation.
  • Subtle conformational differences were observed between monomeric and dimerized TSHR-TMD states.
  • Ligand-binding sites within the dimer exhibited altered conformations, suggesting variable ligand affinities.
  • Docking scores revealed differences in binding affinities for known TSHR agonists and antagonists.

Conclusions:

  • The TSHR-TMD demonstrates a propensity for forming dimeric and oligomeric structures.
  • Dimerization induces conformational changes within the TSHR-TMD that influence the binding characteristics of small molecules.
  • These findings provide deeper insights into TSHR structure-function relationships and potential drug development targets.