5XRA

Crystal structure of the human CB1 in complex with agonist AM11542

Summary for 5XRA

• Entry DOI: 10.2210/pdb5xra/pdb
• Descriptor: Cannabinoid receptor 1,Flavodoxin,Cannabinoid receptor 1, FLAVIN MONONUCLEOTIDE, (6aR,10aR)-3-(8-bromanyl-2-methyl-octan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol, ... (7 entities in total)
• Functional Keywords: membrane protein, human g protein-coupled receptor, stabilizing agonists, lipidic cubic phase, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P21554
• Total number of polymer chains: 1
• Total formula weight: 51304.17

Authors

Hua, T.,Vemuri, K.,Nikas, P.S.,Laprairie, R.B.,Wu, Y.,Qu, L.,Pu, M.,Korde, A.,Shan, J.,Ho, J.H.,Han, G.W.,Ding, K.,Li, X.,Liu, H.,Hanson, M.A.,Zhao, S.,Bohn, L.M.,Makriyannis, A.,Stevens, R.C.,Liu, Z.J. (deposition date: 2017-06-08, release date: 2017-07-12, Last modification date: 2024-11-20)

Primary citation

Hua, T.,Vemuri, K.,Nikas, S.P.,Laprairie, R.B.,Wu, Y.,Qu, L.,Pu, M.,Korde, A.,Jiang, S.,Ho, J.H.,Han, G.W.,Ding, K.,Li, X.,Liu, H.,Hanson, M.A.,Zhao, S.,Bohn, L.M.,Makriyannis, A.,Stevens, R.C.,Liu, Z.J.
Crystal structures of agonist-bound human cannabinoid receptor CB1
Nature, 547:468-471, 2017

PubMed Abstract: The cannabinoid receptor 1 (CB) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ-tetrahydrocannabinol (Δ-THC). Here we report two agonist-bound crystal structures of human CB in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200 and Trp356 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB and provide a molecular basis for predicting the binding modes of Δ-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

PubMed: 28678776
DOI: 10.1038/nature23272

Experimental method

X-RAY DIFFRACTION (2.8 Å)