Cooperative Peripheral CB1 Inhibition by Extracellular Antibody Binding and Orthosteric Antagonism
- 1Shanghai Institute of Materia Medica Chinese Academy of Sciences
Abstract
The cannabinoid receptor CB1 is an important therapeutic target for obesity and metabolic disorders, yet centrally acting CB1 antagonists are limited by neuropsychiatric side effects. Although the anti-CB1 antibody Nimacimab has advanced to Phase 2 clinical trials for metabolic disorders, the molecular mechanisms underlying peripheral CB1 inhibition remain poorly understood. Here, we report cryo-EM structures of human CB1 bound to Nimacimab alone and in complex with the orthosteric antagonists Rimonabant and JD5037. Unlike previously characterized inhibitory GPCR antibodies that block ligand access through steric occlusion or directly engage orthosteric sites, Nimacimab functions through extracellular allosteric inhibition by stabilizing an inactive-like extracellular architecture of CB1. Antibody binding restricts extracellular conformational dynamics and allosterically stabilizes inactive-state signaling microswitches. Importantly, extracellular antibody engagement is structurally compatible with orthosteric antagonism and cooperatively enhances CB1 inhibition. Structural analysis further reveals how JD5037 remodels the extracellular vestibule to achieve peripheral-selective antagonism. Together, these findings establish extracellular allosteric inhibition as a distinct mechanism of GPCR regulation and provide a structural framework for the development of peripherally selective CB1 therapeutics.
Related
- Dual Evidence of Trichoderma pleuroti Antagonism against Pleurotus pulmonarius: Direct Inhibition and Volatile-Mediated Bioassays with Volatilome Fingerprinting.
- Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma
- Lipidomic Profiling of Peripheral Extracellular Vesicles as a Potential Source of Biomarkers in Gaucher Disease
- Comparative effects of central and peripheral PDE10A inhibition on weight gain following semaglutide cessation in diet-induced obese mice
- High salt induces early metabolic and extracellular matrix remodeling in Dahl salt-sensitive rats that persists despite subdepressor ACE inhibition
BibTeX
@misc{y2026cooperative,
title = {{Cooperative Peripheral CB1 Inhibition by Extracellular Antibody Binding and Orthosteric Antagonism}},
author = {Y. GAO and J. WANG and Y. LAI and Y. yue and j. hou and y. bai and x. he and X. ZHANG and w. hu and j. li and H. E. Xu and F. Xu and H. Liu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754614},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754614v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cooperative Peripheral CB1 Inhibition by Extracellular Antibody Binding and Orthosteric Antagonism
AU - Y. GAO
AU - J. WANG
AU - Y. LAI
AU - Y. yue
AU - j. hou
AU - y. bai
AU - x. he
AU - X. ZHANG
AU - w. hu
AU - j. li
AU - H. E. Xu
AU - F. Xu
AU - H. Liu
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754614
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754614v1
AB - The cannabinoid receptor CB1 is an important therapeutic target for obesity and metabolic disorders, yet centrally acting CB1 antagonists are limited by neuropsychiatric side effects. Although the anti-CB1 antibody Nimacimab has advanced to Phase 2 clinical trials for metabolic disorders, the molecular mechanisms underlying peripheral CB1 inhibition remain poorly understood. Here, we report cryo-EM structures of human CB1 bound to Nimacimab alone and in complex with the orthosteric antagonists Rimonabant and JD5037. Unlike previously characterized inhibitory GPCR antibodies that block ligand access through steric occlusion or directly engage orthosteric sites, Nimacimab functions through extracellular allosteric inhibition by stabilizing an inactive-like extracellular architecture of CB1. Antibody binding restricts extracellular conformational dynamics and allosterically stabilizes inactive-state signaling microswitches. Importantly, extracellular antibody engagement is structurally compatible with orthosteric antagonism and cooperatively enhances CB1 inhibition. Structural analysis further reveals how JD5037 remodels the extracellular vestibule to achieve peripheral-selective antagonism. Together, these findings establish extracellular allosteric inhibition as a distinct mechanism of GPCR regulation and provide a structural framework for the development of peripherally selective CB1 therapeutics.
ER -