The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Structure and function of an irreversible agonist-β2 adrenoceptor complex
Open accessAbstract
G-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs, the molecular basis for agonist binding and allosteric modulation of these proteins is poorly understood. Structural knowledge of agonist-bound states is essential for deciphering the mechanism of receptor activation, and for structure-guided design and optimization of ligands. However, the crystallization of agonist-bound GPCRs has been hampered by modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human β2 adrenergic receptor (β2AR) as a guide, we designed a β2AR agonist that can be covalently tethered to a specific site on the receptor through a disulphide bond. The covalent β2AR-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound β2AR–T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method, and determined its structure at 3.5 Å resolution. A comparison to the inactive structure and an antibody-stabilized active structure (companion paper) shows how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures are in agreement with long-timescale (up to 30 μs) molecular dynamics simulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
VMD: visual molecular dynamics
Humphrey, W., Dalke, A., & Schulten, K. (1996) · Journal of Molecular Graphics · doi:10.1016/0263-7855(96)00018-5 · Cited by 66,952
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Palczewski, K., Kumasaka, T., Hori, T., Behnke, C. A., Motoshima, H., Fox, B. A., Trong, I. L., Teller, D. C., Okada, T., Stenkamp, R. E., et al. (2000) · Science · doi:10.1126/science.289.5480.739 · Cited by 5,637
The structure and function of G-protein-coupled receptors
Rosenbaum, D. M., Rasmussen, S. G. F., & Kobilka, B. K. (2009) · Nature · doi:10.1038/nature08144 · Cited by 2,534
Self-citationCrystal structure of opsin in its G-protein-interacting conformation
Scheerer, P., Park, J. H., Hildebrand, P. W., Kim, Y. J., Krauß, N., Choe, H.-W., Hofmann, K. P., & Ernst, O. P. (2008) · Nature · doi:10.1038/nature07330 · Cited by 1,059
Cited by
Crystal structure of the β2 adrenergic receptor–Gs protein complex
Rasmussen, S. G. F., DeVree, B. T., Zou, Y., Kruse, A. C., Chung, K. Y., Kobilka, T. S., Thian, F. S., Chae, P. S., Pardon, E., Calinski, D., et al. (2011) · Nature · doi:10.1038/nature10361 · Cited by 3,009
Self-citationThe Molecular Basis of G Protein–Coupled Receptor Activation
Weis, W. I., & Kobilka, B. K. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-033910 · Cited by 1,227
Self-citationRegulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance
Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S., Koch, T., Evans, C. J., & Christie, M. J. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.005942 · Cited by 802
Emerging paradigms in GPCR allostery: implications for drug discovery
Wootten, D., Christopoulos, A., & Sexton, P. M. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4052 · Cited by 498
Nanobody stabilization of G protein-coupled receptor conformational states
Steyaert, J., & Kobilka, B. K. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.06.011 · Cited by 234
Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist
Masureel, M., Zou, Y., Picard, L.-P., van der Westhuizen, E., Mahoney, J. P., Rodrigues, J. P. G. L. M., Mildorf, T. J., Dror, R. O., Shaw, D. E., Bouvier, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0145-x · Cited by 194
Self-citationDuncan, A. L., Song, W., & Sansom, M. S. P. (2020) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010919-023411 · Cited by 158
β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade
Zhang, F., Gannon, M., Chen, Y., Yan, S., Zhang, S., Feng, W., Tao, J., Sha, B., Liu, Z., Saito, T., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay6931 · Cited by 133
LGR6 Is a High Affinity Receptor of R-Spondins and Potentially Functions as a Tumor Suppressor
Gong, X., Carmon, K. S., Lin, Q., Thomas, A., Yi, J., & Liu, Q. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037137 · Cited by 129
Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations
Hertig, S., Latorraca, N. R., & Dror, R. O. (2016) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1004746 · Cited by 118
Self-citationLabeling and Single-Molecule Methods To Monitor G Protein-Coupled Receptor Dynamics
Tian, H., Fürstenberg, A., & Huber, T. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00084 · Cited by 114
Preininger, A. M., Meiler, J., & Hamm, H. E. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.04.011 · Cited by 104
G Protein-Coupled Receptor Heterocomplexes in Neuropsychiatric Disorders
Moreno, J. L., Holloway, T., & González-Maeso, J. (2013) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-386931-9.00008-8 · Cited by 30
Leemann, S., & Kleinlogel, S. (2023) · doi:10.1101/2023.01.27.525823 · Cited by 2
Metadata
- Authors
- Rosenbaum, D. M., Zhang, C., Lyons, J. A., Holl, R., Aragao, D., Arlow, D. H., Rasmussen, S. G. F., Choi, H.-J., DeVree, B. T., Sunahara, R. K., Chae, P. S., Gellman, S. H., Dror, R. O., Shaw, D. E., Weis, W. I., Caffrey, M., Gmeiner, P., & Kobilka, B. K.
- Venue
- Nature
- Published
- 2011-01
- Volume
- 469
- Issue
- 7329
- Pages
- 236-240
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2168966210
- Cited by
- 767
- References
- 5
- FWCI
- 43.85
- Type
- journal article
- Language
- en
- Open access
- green
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
