ArticleBMC biology2026
Computational design of constitutively active mutants of Dopamine D2 receptor inspired by ligand-independent activation mechanisms.
Article in BMC biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundG protein-coupled receptors (GPCRs) can signal in the absence of agonists through constitutive activity. This activity can be enhanced by mutations, resulting in receptors known as constitutively active mutants (CAMs). Such receptors are implicated in various physiological and pathophysiological conditions, and also offer significant therapeutic potential. However, the molecular basis of their constitutive activity remains unknown.
resultsTo investigate how CAMs affect receptor activation, we employed enhanced sampling simulations to study the dopamine D2 receptor (D2R), a key target in central nervous system therapies. Free energy landscape analyses revealed that CAMs promote a conformational shift favoring an active state similar to the agonist-bound receptor. To then identify novel CAMs, we developed a comprehensive strategy combining structural comparison, in-silico residue scanning, and free energy calculations, validated by luminescence-complementation-based assays. Applied to D2R, this approach uncovered a new single-point CAM, D2R-I48
conclusionsThis study elucidates how CAMs reshape the activation landscape of D2R and establishes a broadly applicable computational-experimental framework for discovering constitutively active GPCR variants. These CAMs provide valuable ligand-independent models for probing receptor activation mechanisms at structural, cellular, and physiological levels.
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