Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain

Isaias Lans, Óscar Díaz, James A.R. Dalton, Jesús Giraldo*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)


As a class C GPCR and regulator of synaptic activity, mGlu5 is an attractive drug target, potentially offering treatment for several neurologic and psychiatric disorders. As little is known about the activation mechanism of mGlu5 at a structural level, potential of mean force calculations linked to molecular dynamics simulations were performed on the mGlu5 transmembrane domain crystal structure to explore various internal mechanisms responsible for its activation. Our results suggest that the hydrophilic interactions between intracellular loop 1 and the intracellular side of TM6 have to be disrupted to reach a theoretically active-like conformation. In addition, interactions between residues that are key for mGlu5 activation (Tyr6593.44 and Ile7515.51) and mGlu5 inactivation (Tyr6593.44 and Ser8097.39) have been identified. Inasmuch as mGlu5 receptor signaling is poorly understood, potentially showing a complex network of micro-switches and subtle structure-activity relationships, the present study represents a step forward in the understanding of mGlu5 transmembrane domain activation.

Original languageEnglish
Article number38
JournalFrontiers in Molecular Biosciences
Publication statusPublished - 6 Mar 2020


  • G protein-coupled receptors
  • class C GPCR
  • free energies
  • mGlu
  • mGlu5 receptor
  • molecular dynamics computer simulation
  • potential of mean force calculations


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