Evaluating Allosteric Perturbations in Cannabinoid Receptor 1 by <i>In Silico</i> Single-Point Mutation

Díaz, Ómar Huertas; Renault, Pedro; Giraldo, Jesús

doi:10.1021/acsomega.2c04980

Cited by 2 publications

(2 citation statements)

References 63 publications

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“…F237 4.46 could potentially attract F155 2.42 via π-bonding to adopt its outward-facing rotamer, loosening the bundle and thus facilitating the outward movement of TM6 and receptor activation [ 23 ]. Furthermore, mutation of F237 4.46 to a lysine (F237L) was found to stabilise an inactive conformation and inhibit agonist-induced activation while not affecting the affinity of CP55940 [ 29 ]. Upon receptor activation, F155 2.42 moves from facing the G protein cavity to face the extrahelical cavity and interacts with L209 3.45 [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, mutation of F237 4.46 to a lysine (F237L) was found to stabilise an inactive conformation and inhibit agonist-induced activation while not affecting the affinity of CP55940 [ 29 ]. Upon receptor activation, F155 2.42 moves from facing the G protein cavity to face the extrahelical cavity and interacts with L209 3.45 [ 29 ]. It is possible that this interaction is disrupted in L209A 3.45 , therefore restricting receptor activation by both orthosteric and allosteric ligands ( Figure 3 and Figure 4 , and Table 2 and Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

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Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies

Green,

Fellner,

Finlay

et al. 2024

Pharmaceuticals

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Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB1) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB1 activation. Here, molecular modeling and mutagenesis were used to identify residues central to PAM activity at CB1. Six putative allosteric binding sites were identified in silico, including novel sites previously associated with cholesterol binding, and key residues within each site were mutated to alanine. The recently determined ZCZ011 binding site was found to be essential for allosteric agonism, as GAT228, GAT229 and ZCZ011 all increased wild-type G protein dissociation in the absence of an orthosteric ligand; activity that was abolished in mutants F191A3.27 and I169A2.56. PAM activity was demonstrated for ZCZ011 in the presence of the orthosteric ligand CP55940, which was only abolished in I169A2.56. In contrast, the PAM activity of GAT229 was reduced for mutants R220A3.56, L404A8.50, F191A3.27 and I169A2.56. This indicates that allosteric modulation may represent the net effect of binding at multiple sites, and that allosteric agonism is likely to be mediated via the ZCZ011 site. This study underlines the need for detailed understanding of ligand receptor interactions in the search for pure CB1 allosteric modulators.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies

Green,

Fellner,

Finlay

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

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GPCR Signaling: A Study of the Interplay Between Structure, Energy, and Function

Chalopin

2024

Proteins

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G protein‐coupled receptors (GPCRs) exemplify sophisticated allosteric communication, transducing extracellular signals through ligand‐induced structural rearrangements that resonate through the molecular scaffold. Despite extensive study, the biophysical underpinnings of how conformational changes spread remain unclear. This work employs a novel physics‐based framework to characterize the role of energy dissipation in directing intramolecular signaling pathways. By modeling each residue as a network of coupled oscillators, we generate a localization landscape depicting the vibrational energy distribution throughout the protein scaffold. Quantifying directional energy flux between residues reveals distinct pathways for energy and information transfer, illuminating sequences of allosteric communication. Our analysis of CB1 and CCR5 crystal structures unveils an anisotropic pattern of energy dissipation aligning with key functional dynamics, such as activation‐related conformational changes. These anisotropic patterns of vibrational energy flow constitute pre‐configured channels for allosteric signaling. Elucidating the relationship between structural topology and energy dissipation patterns provides key insights into the thermodynamic drivers of conformational signaling. This methodology significantly advances our mechanistic understanding of allostery in GPCRs and presents a broadly applicable approach for rationally dissecting allosteric communication pathways, with potential implications for structure‐based drug design targeting these critical receptors.

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Evaluating Allosteric Perturbations in Cannabinoid Receptor 1 by In Silico Single-Point Mutation

Cited by 2 publications

References 63 publications

Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies

Determination of the Cannabinoid CB1 Receptor’s Positive Allosteric Modulator Binding Site through Mutagenesis Studies

GPCR Signaling: A Study of the Interplay Between Structure, Energy, and Function

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