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Asymmetric Dynamics Between the Protomers of the σ2 Receptor Homodimer.

Manming Xu1, Saleh Alyemni1, Veniamin A Borin2

  • 1UCL School of Pharmacy, London WC1N 1AX, U., KUK.

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|November 6, 2025
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The sigma-2 receptor (σ2R/TMEM97) exhibits asymmetric dynamics, crucial for its function in cholesterol regulation. Cholesterol binding enhances this asymmetry, offering insights into receptor activity in diseases.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • The sigma-2 receptor (σ2R/TMEM97) is a membrane protein implicated in cholesterol regulation.
  • Overexpression of σ2R is observed in cancer and neurodegenerative diseases, highlighting its clinical relevance.
  • Understanding σ2R's dynamic mechanisms and ligand interactions is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the conformational dynamics of the σ2R homodimer.
  • To elucidate the role of cholesterol binding in σ2R function.
  • To explore the mechanistic basis of σ2R's dimeric behavior and allosteric modulation.

Main Methods:

  • Adaptive sampling molecular dynamics simulations.
  • Quasi-anharmonic analysis.
  • Unsupervised machine learning for conformational analysis.

Main Results:

  • Revealed asymmetric dynamics between the two σ2R protomers.
  • Identified anticorrelated helical motions and salt bridge switching (K55-E139 and D122-R140) driving asymmetry.
  • Demonstrated that cholesterol binding stabilizes one protomer and alters the other, enhancing asymmetry and membrane coupling.

Conclusions:

  • The study provides mechanistic insights into σ2R function, emphasizing the importance of asymmetric dynamics.
  • Ligand binding at one site may allosterically modulate the apo protomer, explaining the receptor's dimeric nature.
  • Species-specific allosteric interactions (D56-R133) may be vital for human σ2R function.