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Structural and Computational Insights into Dynamics and Intermediate States of Orexin 2 Receptor Signaling

Shun Yokoi1, Ryoji Suno2, Ayori Mitsutake1

  • 1Department of Physics, School of Science and Technology, Meiji University, 1-1-1 Higashi-Mita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan.

The Journal of Physical Chemistry. B
|May 9, 2024
PubMed

Insights

Orexin 2 receptor (OX2R) activation involves collective TM domain motions, particularly TM3 vertical movement. Key residues Q134, V142, and R152 show significant fluctuations, influencing ligand binding and signal selectivity for OX2R drug discovery.

Area of Science:

  • Structural Biology
  • Computational Chemistry
  • Pharmacology

Background:

  • Orexin 2 receptor (OX2R) is a G protein-coupled receptor (GPCR) critical for regulating the sleep-wake cycle.
  • Understanding GPCR activation dynamics and intermediate states is crucial for drug discovery, particularly for precise control of intracellular signaling.
  • Previous studies relied on static structural data, lacking insights into dynamic activation mechanisms.

Purpose of the Study:

  • To investigate the dynamic motions of the Orexin 2 receptor (OX2R) during activation using molecular dynamics (MD) simulations.
  • To identify key residues and structural movements involved in OX2R activation and signaling.
  • To provide insights into intermediate states that could inform the development of biased agonists for OX2R.

Main Methods:

  • Performed 30 independent microsecond-scale molecular dynamics (MD) simulations of various OX2R systems.
  • Applied relaxation mode analysis to identify collective motions within the transmembrane (TM) domain during activation.
  • Analyzed conformational fluctuations of specific amino acid residues on TM3 (Q134, V142, R152) and their relation to TM3 movement.

Main Results:

  • Identified collective motions of the TM domain during OX2R activation, with TM3 exhibiting significant vertical movement relative to the membrane.
  • Highlighted three key residues on TM3 (Q134, V142, R152) with substantial conformational fluctuations that correlate with TM3 movement.
  • Observed that the OX2R-Gi signaling complex stabilizes in a conformation resembling a non-canonical (NC) intermediate state.

Conclusions:

  • The study elucidates dynamic aspects of OX2R activation, revealing TM3's role and specific residue dynamics.
  • Insights into ligand binding recognition and signal selectivity are provided, linked to the equilibrium changes of Q134 and R152.
  • Findings on dynamic intermediate states, including the NC-like state, offer a foundation for designing biased agonists targeting OX2R.

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