The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Activation mechanism of the β2-adrenergic receptor
Open accessAbstract
A third of marketed drugs act by binding to a G-protein-coupled receptor (GPCR) and either triggering or preventing receptor activation. Although recent crystal structures have provided snapshots of both active and inactive functional states of GPCRs, these structures do not reveal the mechanism by which GPCRs transition between these states. Here we propose an activation mechanism for the β2-adrenergic receptor, a prototypical GPCR, based on atomic-level simulations in which an agonist-bound receptor transitions spontaneously from the active to the inactive crystallographically observed conformation. A loosely coupled allosteric network, comprising three regions that can each switch individually between multiple distinct conformations, links small perturbations at the extracellular drug-binding site to large conformational changes at the intracellular G-protein-binding site. Our simulations also exhibit an intermediate that may represent a receptor conformation to which a G protein binds during activation, and suggest that the first structural changes during receptor activation often take place on the intracellular side of the receptor, far from the drug-binding site. By capturing this fundamental signaling process in atomic detail, our results may provide a foundation for the design of drugs that control receptor signaling more precisely by stabilizing specific receptor conformations.
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Cites
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins
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Crystal structure of opsin in its G-protein-interacting conformation
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Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation
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Molecular Dynamics Simulation for All
Hollingsworth, S. A., & Dror, R. O. (2018) · Neuron · doi:10.1016/j.neuron.2018.08.011 · Cited by 3,257
Self-citationThe Molecular Basis of G Protein–Coupled Receptor Activation
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GPCR Dynamics: Structures in Motion
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Self-citationCommon activation mechanism of class A GPCRs
Zhou, Q., Yang, D., Wu, M., Guo, Y., Guo, W., Zhong, L., Cai, X., Dai, A., Jang, W., Shakhnovich, E. I., et al. (2019) · eLife · doi:10.7554/elife.50279 · Cited by 632
Structure-based discovery of nonhallucinogenic psychedelic analogs
Cao, D., Yu, J., Wang, H., Luo, Z., Liu, X., He, L., Qi, J., Fan, L., Tang, L., Chen, Z., et al. (2022) · Science · doi:10.1126/science.abl8615 · Cited by 312
Metadata
- Authors
- Dror, R. O., Arlow, D. H., Maragakis, P., Mildorf, T. J., Pan, A. C., Xu, H., Borhani, D. W., & Shaw, D. E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2011-10-26
- Volume
- 108
- Issue
- 46
- Pages
- 18684-18689
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1997340548
- Cited by
- 623
- References
- 41
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- green
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- Dror, R. O., Arlow, D. H., Maragakis, P., Mildorf, T. J., Pan, A. C., Xu, H., Borhani, D. W., & Shaw, D. E. (2011). Activation mechanism of the β2-adrenergic receptor. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1110499108
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