ArticleProceedings of the National Academy of Sciences of the United States of America2019
Structural basis for ligand modulation of the CCR2 conformational landscape.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 50 citations in OpenAlex.
- A Minimalist Model for Navigating Conformational Landscape Uncovers the Activation Mechanism of βACS physical chemistry Au · 2026Article
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- Molecular basis of ligand binding and receptor activation at the human ANature communications · 2025Article
- Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease.Science signaling · 2024Article
- Identification of immune-associated biomarkers of diabetes nephropathy tubulointerstitial injury based on machine learning: a bioinformatics multi-chip integrated analysis.BioData mining · 2024Article
- Activation mechanism of the human Smoothened receptor.Biophysical journal · 2023Article
- Cryo-EM structures of orphan GPR21 signaling complexes.Nature communications · 2023Article
- Role of G-protein coupled receptors in cardiovascular diseases.Frontiers in cardiovascular medicine · 2023Review
- Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.Nature chemical biology · 2022Article
- Fewer Dimensions, More Structures for Improved Discrete Models of Dynamics of Free versus Antigen-Bound Antibody.Biomolecules · 2022Article
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design.Nature communications · 2021Article
- Independent Markov decomposition: Toward modeling kinetics of biomolecular complexes.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2.Journal of medicinal chemistry · 2021Article
- Macrophage lineages in heart valve development and disease.Cardiovascular research · 2021Review
- Role of Chemokines in the Biology of Cholangiocarcinoma.Cancers · 2020Review
- Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.Science (New York, N.Y.) · 2020Article
- Deficiency of Circulating Monocytes Ameliorates the Progression of Myxomatous Valve Degeneration in Marfan Syndrome.Circulation · 2020Article
- Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor.PloS one · 2020Article
- Structural basis for ligand modulation of the CCR2 conformational landscape.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
CC chemokine receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands, named for the adjacent cysteine motif on their N terminus. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. CCR2, in particular, promotes the metastasis of cancer cells and is also implicated in autoimmunity-driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long-timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation and disrupt a continuous internal water and sodium ion pathway, preventing transitions to an active-like state. Several metastable conformations present a cryptic drug-binding pocket near the allosteric site that may be amenable to targeting with small molecules. Without antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2 and may also be useful for future drug design.
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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.