ArticleBiochimica et biophysica acta2015
A mechanistic role of Helix 8 in GPCRs: Computational modeling of the dopamine D2 receptor interaction with the GIPC1-PDZ-domain.
Article in Biochimica et biophysica acta, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Cooperative Control of Arrestin Activation By Membrane Lipids And Phosphorylation Barcodes.bioRxiv : the preprint server for biology · 2026Article
- G-protein-coupled receptor diversity and evolution in the closest living relatives of metazoa.eLife · 2025Article
- Insights on the G protein-coupled receptor helix 8 solution structure and orientation using a neurotensin receptor 1 peptide.Protein science : a publication of the Protein Society · 2024Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- All-Atom Molecular Dynamics Investigations on the Interactions between D2 Subunit Dopamine Receptors and ThreeInternational journal of molecular sciences · 2022Article
- Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology.Pharmacological reports : PR · 2021Review
- DEER Analysis of GPCR Conformational Heterogeneity.Biomolecules · 2021Review
- Lipid nanoparticle technologies for the study of G protein-coupled receptors in lipid environments.Biophysical reviews · 2020Review
- Conformational dynamics of a G protein-coupled receptor helix 8 in lipid membranes.Science advances · 2020Article
- Article
- Lipid rafts are required for effective renal DFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology.Current neuropharmacology · 2020Review
- Protein Interactors and Trafficking Pathways That Regulate the Cannabinoid Type 1 Receptor (CB1R).Frontiers in molecular neuroscience · 2020Review
- JMJD3 regulates CD4 T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4.The Journal of clinical investigation · 2019Article
- Apelinergic System Structure and Function.Comprehensive Physiology · 2017Review
- A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway.Molecular neurodegeneration · 2017Article
- ACTH Receptor (MC2R) Specificity: What Do We Know About Underlying Molecular Mechanisms?Frontiers in endocrinology · 2017Review
- The Atypical Receptor CCRL2 (C-C Chemokine Receptor-Like 2) Does Not Act As a Decoy Receptor in Endothelial Cells.Frontiers in immunology · 2017Article
- Frizzled-4 C-terminus Distal to KTXXXW Motif is Essential for Normal Dishevelled Recruitment and Norrin-stimulated Activation of Lef/Tcf-dependent Transcriptional Activation.Journal of molecular signaling · 2016Article
- A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling.Molecular and cellular biology · 2016Article
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2 authors.
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Abstract
Helix-8 (Hx8) is a structurally conserved amphipathic helical motif in class-A GPCRs, adjacent to the C-terminal sequence that is responsible for PDZ-domain-recognition. The Hx8 segment in the dopamine D2 receptor (D2R) constitutes the C-terminal segment and we investigate its role in the function of D2R by studying the interaction with the PDZ-containing GIPC1 using homology models based on the X-ray structures of very closely related analogs: the D3R for the D2R model, and the PDZ domain of GIPC2 for GIPC1-PDZ. The mechanism of this interaction was investigated with all-atom unbiased molecular dynamics (MD) simulations that reveal the role of the membrane in maintaining the helical fold of Hx8, and with biased MD simulations to elucidate the energy drive for the interaction with the GIPC1-PDZ. We found that it becomes more favorable energetically for Hx8 to adopt the extended conformation observed in all PDZ-ligand complexes when it moves away from the membrane, and that C-terminus palmitoylation of D2R enhanced membrane penetration by the Hx8 backbone. De-palmitoylation enables Hx8 to move out into the aqueous environment for interaction with the PDZ domain. All-atom unbiased MD simulations of the full D2R-GIPC1-PDZ complex in sphingolipid/cholesterol membranes show that the D2R carboxyl C-terminus samples the region of the conserved GFGL motif located on the carboxylate-binding loop of the GIPC1-PDZ, and the entire complex distances itself from the membrane interface. Together, these results outline a likely mechanism of Hx8 involvement in the interaction of the GPCR with PDZ-domains in the course of signaling.
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