ArticleProceedings of the National Academy of Sciences of the United States of America2014
Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. 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, 44 citations in OpenAlex.
- Steviol rebaudiosides bind to four different sites of the human sweet taste receptor (T1R2/T1R3) complex explaining confusing experiments.Communications chemistry · 2024Article
- The chemokine receptor CCR5: multi-faceted hook for HIV-1.Retrovirology · 2024Review
- Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery.Nature communications · 2023Article
- Article
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment.The journal of physical chemistry letters · 2021Article
- Modeling of CCR5 Recognition by HIV-1 gp120: How the Viral Protein Exploits the Conformational Plasticity of the Coreceptor.Viruses · 2021Article
- Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HTPharmaceuticals (Basel, Switzerland) · 2021Article
- Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.QRB discovery · 2021Article
- Non-full-length Water-Soluble CXCR4iScience · 2020Article
- Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods.International journal of molecular sciences · 2019Article
- Molecular binding mode of PF-232798, a clinical anti-HIV candidate, at chemokine receptor CCR5.Acta pharmacologica Sinica · 2019Article
- Modulation of allosteric coupling by mutations: from protein dynamics and packing to altered native ensembles and function.Current opinion in structural biology · 2019Review
- CCR5 structural plasticity shapes HIV-1 phenotypic properties.PLoS pathogens · 2018Article
- Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- mutLBSgeneDB: mutated ligand binding site gene DataBase.Nucleic acids research · 2017Article
- Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation.Biophysical journal · 2016Article
- Short Communication: Limited Anti-HIV-1 Activity of Maraviroc in Mucosal Tissues.AIDS research and human retroviruses · 2016Article
- Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications.PLoS computational biology · 2016Article
- Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.Journal of chemical information and modeling · 2016Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We predicted the structural basis for pleiotropic signaling of the C-C chemokine type 5 (CCR5) G protein-coupled receptor (GPCR) by predicting the binding of several ligands to the lower-energy conformations of the CCR5 receptor and 11 mutants. For each case, we predicted the ∼ 20 most stable conformations for the receptor along with the binding sites for four anti-HIV ligands. We found that none of the ligands bind to the lowest-energy apo-receptor conformation. The three ligands with a similar pharmacophore (Maraviroc, PF-232798, and Aplaviroc) bind to a specific higher-energy receptor conformation whereas TAK-779 (with a different pharmacophore) binds to a different high-energy conformation. This result is in agreement with the very different binding-site profiles for these ligands obtained by us and others. The predicted Maraviroc binding site agrees with the recent structure of CCR5 receptor cocrystallized with Maraviroc. We performed 11 site-directed mutagenesis experiments to validate the predicted binding sites. Here, we independently predicted the lowest 10 mutant protein conformations for each of the 11 mutants and then docked the ligands to these lowest conformations. We found the predicted binding energies to be in excellent agreement with our mutagenesis experiments. These results show that, for GPCRs, each ligand can stabilize a different protein conformation, complicating the use of cocrystallized structures for ligand screening. Moreover, these results show that a single-point mutation in a GPCR can dramatically alter the available low-energy conformations, which in turn alters the binding site, potentially altering downstream signaling events. These studies validate the conformational selection paradigm for the pleiotropic function and structural plasticity of GPCRs.
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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.