ArticleProceedings of the National Academy of Sciences of the United States of America2010
Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 69 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
69 citing papers in PubMed, 105 citations in OpenAlex.
- DIVERGE v4: A Platform for Large-Scale Analysis of Functional Divergence Across Multi-Gene Families.Molecular biology and evolution · 2025Article
- Structure and dynamics determine G protein coupling specificity at a class A GPCR.Science advances · 2025Article
- Evolutionary scenarios for the specific recognition of nonhomologous endogenous peptides by G protein-coupled receptor paralogs.The Journal of biological chemistry · 2025Article
- A parameterized two-domain thermodynamic model explains diverse mutational effects on protein allostery.eLife · 2024Article
- A parametrized two-domain thermodynamic model explains diverse mutational effects on protein allostery.bioRxiv : the preprint server for biology · 2024Article
- Evolutionary selection of proteins with two folds.Nature communications · 2023Article
- Evolutionary selection of proteins with two folds.bioRxiv : the preprint server for biology · 2023Article
- Genome interpretation using in silico predictors of variant impact.Human genetics · 2022Review
- Odd one out? Functional tuning of Zymomonas mobilis pyruvate kinase is narrower than its allosteric, human counterpart.Protein science : a publication of the Protein Society · 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
- Identification of evolutionarily stable functional and immunogenic sites across the SARS-CoV-2 proteome and greater coronavirus family.Bioinformatics (Oxford, England) · 2021Article
- Uncovering DNA-PKcs ancient phylogeny, unique sequence motifs and insights for human disease.Progress in biophysics and molecular biology · 2021Article
- Allosteric communication regulates ligand-specific GPCR activity.The FEBS journal · 2021Review
- Identification of evolutionarily stable functional and immunogenic sites across the SARS-CoV-2 proteome and the greater coronavirus family.Research square · 2021Article
- Structure and evolutionary trace-assisted screening of a residue swapping the substrate ambiguity and chiral specificity in an esterase.Computational and structural biotechnology journal · 2021Article
- Decoding Cancer Variants of Unknown Significance for Helicase-Nuclease-RPA Complexes Orchestrating DNA Repair During Transcription and Replication.Frontiers in molecular biosciences · 2021Article
- Unraveling the molecular basis of host cell receptor usage in SARS-CoV-2 and other human pathogenic β-CoVs.Computational and structural biotechnology journal · 2021Article
- An Evolutionary Trace method defines functionally important bases and sites common to RNA families.PLoS computational biology · 2020Article
- Computational design of G Protein-Coupled Receptor allosteric signal transductions.Nature chemical biology · 2020Article
- Common activation mechanism of class A GPCRs.eLife · 2019Article
9 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
G protein-coupled receptors for dopamine and serotonin control signaling pathways targeted by many psychoactive drugs. A puzzle is how receptors with similar functions and nearly identical binding site structures, such as D2 dopamine receptors and 5-HT2A serotonin receptors, could evolve a mechanism that discriminates stringently in their cellular responses between endogenous neurotransmitters. We used the Difference Evolutionary Trace (Difference-ET) and residue-swapping to uncover two distinct sets of specificity-determining sequence positions. One at the ligand-binding pocket determines the relative affinities for these two ligands, and a distinct, surprising set of positions outside the binding site determines whether a bound ligand can trigger the conformational rearrangement leading to G protein activation. Thus one site specifies affinity while the other encodes a filter for efficacy. These findings demonstrate that allosteric pathways linking distant interactions via alternate conformational states enforce specificity independently of the ligand-binding site, such that either one may be rationally rekeyed to different ligands. The conversion of a dopamine receptor effectively into a serotonin receptor illustrates the plasticity of GPCR signaling during evolution, or in pathological states, and suggests new approaches to drug discovery, targeting both classes of sites.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.