Distinct Binding Mechanisms for Allosteric Sodium Ion in Cannabinoid Receptors
Open accessPublished version of a preprint
Abstract
Abstract The therapeutical potential of Cannabinoid receptors is not fully explored due to psychoactive side-effects and lack of selectivity associated with the orthosteric ligands. Allosteric modulators have the potential to become selective therapeutics for cannabinoid receptors. Biochemical experiments have shown the effects of the allosteric Na + binding on cannabinoid receptor activity. However, the Na + coordination site, and binding pathway are still unknown. Here, we perform molecular dynamic simulations to explore Na + binding in the cannabinoid receptors, CB 1 and CB 2 . Simulations reveal that Na + binds to the primary binding site from different extracellular sites for CB 1 and CB 2 . A distinct secondary Na + coordinate site is identified that is not present in CB 2 . Furthermore, simulations also show that intracellular Na + could bind to the Na + binding site in CB 1 . Constructed Markov state models show that the standard free energy of Na + binding is similar to the previously calculated free energy for other class A GPCRs.
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Cites
Structure and dynamics of GPCR signaling complexes
Hilger, D., Masureel, M., & Kobilka, B. K. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-017-0011-7 · Cited by 969 · see citing works
Markov state models of biomolecular conformational dynamics
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Self-citationTowards simple kinetic models of functional dynamics for a kinase subfamily
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- Authors
- Dutta, S., Selvam, B., & Shukla, D.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Shukla, Diwakar
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-01-12
- Volume
- 13
- Issue
- 3
- Pages
- 379-389
- ISSN
- 1948-7193 (ISSN-L)
- OpenAlex
- W4220988597
- Cited by
- 31
- References
- 4
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 8 · 2022: 4 · 2021: 1
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ACS Chemical Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Division of Molecular and Cellular Biosciences (MCB-1845606)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- cannabinoid receptors, CB1 receptor, CB2 receptor, class A GPCRs, allosteric modulators, binding free energy, Markov state models, receptor selectivity
- MeSH terms
- Allosteric Regulation, Binding Sites, Ligands, Sodium, Receptors, Cannabinoid, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Molecular Dynamics Simulation
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