ArticleProceedings of the National Academy of Sciences of the United States of America2016
Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Molecular mechanisms of native ligand selectivity in catecholamine G protein-coupled receptors.Nature communications · 2026Article
- Allosteric Modulators of Dopamine DMolecules (Basel, Switzerland) · 2022Review
- Extracting phylogenetic dimensions of coevolution reveals hidden functional signals.Scientific reports · 2022Article
- Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Membrane Nanoscopic Organization of D2L Dopamine Receptor Probed by Quantum Dot Tracking.Membranes · 2021Article
- Allosteric communication regulates ligand-specific GPCR activity.The FEBS journal · 2021Review
- Next-generation GRAB sensors for monitoring dopaminergic activity in vivo.Nature methods · 2020Article
- Computational design of G Protein-Coupled Receptor allosteric signal transductions.Nature chemical biology · 2020Article
- Common activation mechanism of class A GPCRs.eLife · 2019Article
- Residues and residue pairs of evolutionary importance differentially direct signaling bias of D2 dopamine receptors.The Journal of biological chemistry · 2019Article
- G-protein-coupled receptor-based sensors for imaging neurochemicals with high sensitivity and specificity.Journal of neurochemistry · 2019Review
- Structure-function analysis of Sedolisins: evolution of tripeptidyl peptidase and endopeptidase subfamilies in fungi.BMC bioinformatics · 2018Article
- Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study.Molecules (Basel, Switzerland) · 2018Article
- Reprogramming G protein coupled receptor structure and function.Current opinion in structural biology · 2018Review
- Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- MISTIC2: comprehensive server to study coevolution in protein families.Nucleic acids research · 2018Article
- Applications of sequence coevolution in membrane protein biochemistry.Biochimica et biophysica acta. Biomembranes · 2018Review
- Discovery of 7-hydroxyaporphines as conformationally restricted ligands for beta-1 and beta-2 adrenergic receptors.MedChemComm · 2018Article
- Power law tails in phylogenetic systems.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Evolutionary action and structural basis of the allosteric switch controlling βNature communications · 2017Article
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Authors and funding
5 authors.
Funding
Abstract
The structural basis of allosteric signaling in G protein-coupled receptors (GPCRs) is important in guiding design of therapeutics and understanding phenotypic consequences of genetic variation. The Evolutionary Trace (ET) algorithm previously proved effective in redesigning receptors to mimic the ligand specificities of functionally distinct homologs. We now expand ET to consider mutual information, with validation in GPCR structure and dopamine D2 receptor (D2R) function. The new algorithm, called ET-MIp, identifies evolutionarily relevant patterns of amino acid covariations. The improved predictions of structural proximity and D2R mutagenesis demonstrate that ET-MIp predicts functional interactions between residue pairs, particularly potency and efficacy of activation by dopamine. Remarkably, although most of the residue pairs chosen for mutagenesis are neither in the binding pocket nor in contact with each other, many exhibited functional interactions, implying at-a-distance coupling. The functional interaction between the coupled pairs correlated best with the evolutionary coupling potential derived from dopamine receptor sequences rather than with broader sets of GPCR sequences. These data suggest that the allosteric communication responsible for dopamine responses is resolved by ET-MIp and best discerned within a short evolutionary distance. Most double mutants restored dopamine response to wild-type levels, also suggesting that tight regulation of the response to dopamine drove the coevolution and intramolecular communications between coupled residues. Our approach provides a general tool to identify evolutionary covariation patterns in small sets of close sequence homologs and to translate them into functional linkages between residues.
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