The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Pathway and mechanism of drug binding to G-protein-coupled receptors
Open accessAbstract
How drugs bind to their receptors—from initial association, through drug entry into the binding pocket, to adoption of the final bound conformation, or “pose”—has remained unknown, even for G-protein-coupled receptor modulators, which constitute one-third of all marketed drugs. We captured this pharmaceutically critical process in atomic detail using the first unbiased molecular dynamics simulations in which drug molecules spontaneously associate with G-protein-coupled receptors to achieve final poses matching those determined crystallographically. We found that several beta blockers and a beta agonist all traverse the same well-defined, dominant pathway as they bind to the β 1 - and β 2 -adrenergic receptors, initially making contact with a vestibule on each receptor’s extracellular surface. Surprisingly, association with this vestibule, at a distance of 15 Å from the binding pocket, often presents the largest energetic barrier to binding, despite the fact that subsequent entry into the binding pocket requires the receptor to deform and the drug to squeeze through a narrow passage. The early barrier appears to reflect the substantial dehydration that takes place as the drug associates with the vestibule. Our atomic-level description of the binding process suggests opportunities for allosteric modulation and provides a structural foundation for future optimization of drug–receptor binding and unbinding rates.
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Cites
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins
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High-Resolution Crystal Structure of an Engineered Human β 2 -Adrenergic G Protein–Coupled Receptor
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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
Structure of a β1-adrenergic G-protein-coupled receptor
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GPCR Engineering Yields High-Resolution Structural Insights into β 2 -Adrenergic Receptor Function
Rosenbaum, D. M., Cherezov, V., Hanson, M. A., Rasmussen, S. G. F., Thian, F. S., Kobilka, T. S., Choi, H.-J., Yao, X.-J., Weis, W. I., Stevens, R. C., et al. (2007) · Science · doi:10.1126/science.1150609 · Cited by 1,336
Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
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Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force
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Allosteric Modulation of G Protein–Coupled Receptors
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How Does a Drug Molecule Find Its Target Binding Site?
Shan, Y., Kim, E. T., Eastwood, M. P., Dror, R. O., Seeliger, M. A., & Shaw, D. E. (2011) · Journal of the American Chemical Society · doi:10.1021/ja202726y · Cited by 614
Self-citation
Cited by
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-citationRole of Molecular Dynamics and Related Methods in Drug Discovery
De Vivo, M., Masetti, M., Bottegoni, G., & Cavalli, A. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01684 · Cited by 1,297
Protein 3D Structure Computed from Evolutionary Sequence Variation
Marks, D. S., Colwell, L. J., Sheridan, R., Hopf, T. A., Pagnani, A., Zecchina, R., & Sander, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028766 · Cited by 1,144
GPCR Dynamics: Structures in Motion
Latorraca, N. R., Venkatakrishnan, A. J., & Dror, R. O. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00177 · Cited by 835
Self-citationSalmaso, V., & Moro, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00923 · Cited by 666
Metadata
- Authors
- Dror, R. O., Pan, A. C., Arlow, D. H., Borhani, D. W., Maragakis, P., Shan, Y., Xu, H., & Shaw, D. E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2011-07-21
- Volume
- 108
- Issue
- 32
- Pages
- 13118-13123
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2049617698
- Cited by
- 730
- References
- 32
- FWCI
- 19.16
- Type
- journal article
- Language
- en
- Open access
- green
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- Dror, R. O., Pan, A. C., Arlow, D. H., Borhani, D. W., Maragakis, P., Shan, Y., Xu, H., & Shaw, D. E. (2011). Pathway and mechanism of drug binding to G-protein-coupled receptors. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1104614108
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