The World of GPCR dimers – Mapping dopamine receptor D2 homodimers in different activation states and configuration arrangements

Bueschbell, Beatriz; Magalhães, Pedro R.; Barreto, Carlos A.V.; Melo, Rita; Schiedel, Anke C.; Machuqueiro, Miguel; Moreira, Irina S.

doi:10.1016/j.csbj.2023.08.032

Cited by 2 publications

References 151 publications

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pK_a Calculations of GPCRs: Understanding Protonation States in Receptor Activation

Barreto,

Vitorino,

Reis

et al. 2024

J. Chem. Inf. Model.

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The increase in the available G protein-coupled receptor (GPCR) structures has been pivotal in helping to understand their activation process. However, the role of protonation−conformation coupling in GPCR activation still needs to be clarified. We studied the protonation behavior of the highly conserved Asp 2.50 residue in five different class A GPCRs (active and inactive conformations) using a linear response approximation (LRA) pK a calculation protocol. We observed consistent differences (1.3 pK units) for the macroscopic pK a values between the inactive and active states of the A2AR and B2AR receptors, indicating the protonation of Asp 2.50 during GPCR activation. This process seems to be specific and not conserved, as no differences were observed in the pK a values of the remaining receptors (CB1R, NT1R, and GHSR).

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pK_a Calculations of GPCRs: Understanding Protonation States in Receptor Activation

Barreto,

Vitorino,

Reis

et al. 2024

J. Chem. Inf. Model.

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Stabilised D₂R G-protein coupled receptor oligomers identify multi-state β-arrestin complexes

Sharrocks,

Fanelli,

Lui

et al. 2024

Preprint

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The G-protein coupled receptor (GPCR) superfamily directs central roles in many physiological and pathophysiological processes via diverse and complex mechanisms. GPCRs can exhibit signal pleiotropy via formation of di/oligomers both with themselves and other GPCRs. A deeper understanding of the molecular basis and functional role of oligomerization would facilitate rational design of activity-selective ligands. A structural model of the D2 dopamine receptor (D2R) homomer identified distinct combinations of substitutions likely to stabilise protomer interactions. Molecular modelling of β-arrestin-2 (βarr2) bound to predicted dimer models suggests a 2:2 receptor:βarr2 stoichiometry, with the dimer favouring βarr2 over Gαi coupling. A combination of biochemical, biophysical and super-resolution, single molecule imaging approaches demonstrated that the D2R mutant homomers exhibited greater stability. The mutant D2R homomers also exhibited bias towards recruitment of the GPCR adaptor protein βarr2 with either faster or ligand-independent βarr2 recruitment, increased internalization and reprogrammed ERK signaling compared to D2R WT. Through GPCR dimer-stabilisation, we demonstrate that D2R di/oligomerization has a role in βarr2-biased signaling.

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The World of GPCR dimers – Mapping dopamine receptor D2 homodimers in different activation states and configuration arrangements

Cited by 2 publications

References 151 publications

pK_a Calculations of GPCRs: Understanding Protonation States in Receptor Activation

pK_a Calculations of GPCRs: Understanding Protonation States in Receptor Activation

Stabilised D₂R G-protein coupled receptor oligomers identify multi-state β-arrestin complexes

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The World of GPCR dimers – Mapping dopamine receptor D2 homodimers in different activation states and configuration arrangements

Cited by 2 publications

References 151 publications

pKa Calculations of GPCRs: Understanding Protonation States in Receptor Activation

pKa Calculations of GPCRs: Understanding Protonation States in Receptor Activation

Stabilised D2R G-protein coupled receptor oligomers identify multi-state β-arrestin complexes

Contact Info

Product

Resources

About

pK_a Calculations of GPCRs: Understanding Protonation States in Receptor Activation

pK_a Calculations of GPCRs: Understanding Protonation States in Receptor Activation

Stabilised D₂R G-protein coupled receptor oligomers identify multi-state β-arrestin complexes