Kumari, Punita and Dvorácskó, Szabolcs and Enos, Michael D. and Ramesh, Karthik and Lim, Darrix and Hassan, Sergio A. and Kunos, George and Cinar, Resat and Iyer, Malliga R. and Rosenbaum, Daniel M. (2024) Structural mechanism of CB1R binding to peripheral and biased inverse agonists. NATURE COMMUNICATIONS, 15 (1). No.-10694. ISSN 2041-1723
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Abstract
The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CB1R inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CB1R inhibitors while sparing the negative psychiatric effects. To understand the mechanism of binding and inhibition of CB1R by peripherally restricted antagonists, we developed a nanobody/fusion protein strategy for high-resolution cryo-EM structure determination of the GPCR inactive state, and used this method to determine structures of CB1R bound to either MRI-1867 or MRI-1891. These structures reveal how these compounds retain high affinity and specificity for CB1R's hydrophobic orthosteric site despite incorporating polar functionalities that lead to peripheral restriction. Further, the structure of the MRI-1891 complex along with accompanying molecular dynamics simulations shows how differential engagement with transmembrane helices and the proximal N-terminus can propagate through the receptor to contribute to biased inhibition of beta-arrestin signaling.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: U.S. Department of Health & Human Services | National Institutes of Health (NIH) [I-1770]; Welch Foundation [R35GM116387]; National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism [IISERB/RD/2024-25/66]; IISER Bhopal [RP170644]; CPRIT Core Facility Support Award Funding text: This work was supported by the Welch Foundation (I-1770 to DMR), the National Institutes of Health (R35GM116387 to DMR), intramural funds of the National Institute on Alcohol Abuse and Alcoholism (to GK, RC, and MRI), and a Start-up Grant from IISER Bhopal (IISERB/R&D/2024-25/66 to PK). Cryo-EM data were collected at the UT Southwestern Medical Center Cryo-EM Facility, which is funded by the CPRIT Core Facility Support Award RP170644. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). |
| Uncontrolled Keywords: | RECEPTOR; SYNTHASE; CRYSTAL-STRUCTURE; INSIGHTS; rimonabant; Dynamic process; |
| Subjects: | Q Science / természettudomány > QD Chemistry / kémia Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 25 Sep 2025 07:46 |
| Last Modified: | 25 Sep 2025 07:46 |
| URI: | https://real.mtak.hu/id/eprint/225269 |
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