Two 2025 crystal structures show human cannabinoid receptor 1 (CB1) bound to cannabinoid agonists, revealing a tighter ligand-binding pocket and structural changes linked to G-protein signaling. The findings offer a molecular view of receptor activation—not evidence that either compound is a treatment or produces a clinical benefit.
What the researchers captured
Tian Hua and colleagues reported two agonist-bound structures of human CB1 in a Nature paper published online on 27 August 2025. One structure contains AM11542, described in the paper as a tetrahydrocannabinol; the other contains AM841, described as a hexahydrocannabinol.
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The structures were determined at 2.80 Å resolution for CB1–AM11542 and 2.95 Å for CB1–AM841. The authors report that the two agonist-bound receptor conformations are similar. These are snapshots of receptor–ligand complexes, rather than a recording of a receptor moving in real time.
How agonist binding changes CB1’s shape
A smaller ligand-binding pocket
Compared with the antagonist-bound structure used as an inactive-state reference, the ligand-binding pocket in the agonist-bound comparison is more compact. The study reports a decrease in pocket volume from 822 ų to 384 ų—a 53% reduction, according to the authors. These are structural measurements from the compared receptor complexes, not measurements of cannabinoid effects in people.
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A changed surface for G-protein binding
The authors report that helix VI moves outward by about 8 Å and that the surface area of the receptor’s G-protein-binding region increases. This arrangement is associated with the receptor’s signaling state: it helps explain how an activated receptor may accommodate a signaling partner. A structural association does not establish a therapeutic effect.
The proposed “twin toggle switch”
Hua and colleagues propose that coordinated movements of two amino-acid residues, Phe200 and Trp356, contribute to CB1 activation. They call this paired mechanism a “twin toggle switch.” It is the authors’ molecular explanation for the structural changes they observe; the structures alone do not show that the mechanism leads to a particular outcome in patients.
What the cholesterol observation does—and doesn’t—show
A cholesterol molecule appears between helices II, III, and IV in both agonist-bound complexes. Its position is an observation in the structures. That observation by itself does not establish what cholesterol does to CB1 function or whether it is necessary for activation.
Where to inspect the structures
The atomic coordinates are deposited in the Protein Data Bank. Researchers and interested readers can view the deposited models by searching these accession IDs:
- 5XRA: CB1 bound to AM11542.
- 5XR8: CB1 bound to AM841.
The authors say the structures provide insight into CB1’s activation mechanism and a molecular basis for predicting binding modes of Δ9-THC and endogenous and synthetic cannabinoids. Those predictions are a research use of the structures, not proof that a compound will have a particular effect in the body.
Keep the 2025 paper distinct from a retracted 2017 article
Nature’s record for the 2025 study also identifies a retraction notice for an earlier 2017 Nature article that had the same title. The 2025 paper is a separate publication with DOI 10.1038/s41586-025-09454-5; the 2017 article had DOI 10.1038/nature23272. The two publication records should not be conflated.
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