ArticleProceedings of the National Academy of Sciences of the United States of America2012
Naturally evolved G protein-coupled receptors adopt metastable conformations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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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
30 citing papers in PubMed, 49 citations in OpenAlex.
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- Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The metastable states of proteins.Protein science : a publication of the Protein Society · 2020Review
- Theoretical identification of thermostabilizing amino acid mutations for G-protein-coupled receptors.Biophysical reviews · 2020Review
- Computational design of G Protein-Coupled Receptor allosteric signal transductions.Nature chemical biology · 2020Article
- Tailor-made GPCRs.Nature chemical biology · 2020Article
- Prediction of Conformation Specific Thermostabilizing Mutations for Class A G Protein-Coupled Receptors.Journal of chemical information and modeling · 2019Article
- Reprogramming G protein coupled receptor structure and function.Current opinion in structural biology · 2018Review
- Computational design of thermostabilizing point mutations for G protein-coupled receptors.eLife · 2018Article
- Computational design of membrane proteins using RosettaMembrane.Protein science : a publication of the Protein Society · 2018Article
- Reprogramming cellular functions with engineered membrane proteins.Current opinion in biotechnology · 2017Review
- Computational design of ligand-binding membrane receptors with high selectivity.Nature chemical biology · 2017Article
- Micro-scale and rapid expression screening of highly expressed and/or stable membrane protein variants in Saccharomyces cerevisiae.Protein science : a publication of the Protein Society · 2016Article
- Toward high-resolution computational design of the structure and function of helical membrane proteins.Nature structural & molecular biology · 2016Article
- A topological and conformational stability alphabet for multipass membrane proteins.Nature chemical biology · 2016Article
- How Can Mutations Thermostabilize G-Protein-Coupled Receptors?Trends in pharmacological sciences · 2016Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
A wide range of membrane receptors signal through conformational changes, and the resulting protein conformational flexibility often hinders their structural studies. Because the determinants of membrane receptor conformational stability are still poorly understood, identifying a minimal set of perturbations stabilizing a membrane protein in a given conformation remains a major challenge in membrane protein structure determination. We present a novel approach integrating bioinformatics, computational design and experimental techniques that identifies and stabilizes metastable receptor regions. When applied to the beta1-adrenergic receptor, the method generated 13 novel receptor variants stabilized in the intended inactive state among which two exhibit an apparent thermostability higher than WT and M23 (a receptor variant previously stabilized by extensive scanning mutagenesis) by more than 30 °C and 11 °C, respectively. Targeted regions involve nonconserved unsatisfied polar residues or exhibit significant packing defects, features found in all class A G protein-coupled receptor structures. These findings suggest that natural G protein-coupled receptor sequences have evolved to be conformationally metastable through the design of suboptimal polar and van der Waals tertiary interactions. Given sufficiently accurate structural models, our approach should prove useful for designing stabilized variants of many uncharacterized membrane receptors.
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