Ligand-binding architecture of human CB2 cannabinoid receptor: evidence for receptor subtype-specific binding motif and modeling GPCR activation.
The extensive physiological influence of transmission through the CB2 cannabinoid receptor makes this G protein-coupled receptor (GPCR) a promising therapeutic target for treating neuropathic pain, inflammation, and immune disorders. However, there is little direct structural information pertaining to either GPCR or CB2-receptor ligand recognition and activation. The present work helps characterize experimentally the ligand-binding interactions of the human CB2 (hCB2) receptor. This study illustrates how our overall experimental approach, "ligand-assisted protein structure" (LAPS), affords direct determination of the requirements for ligand binding to the hCB2 receptor and discrimination among the binding motifs for ligands that activate therapeutically relevant GPCRs.
Pei
Ying
Y
School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Mercier
Richard W
RW
Anday
Jenine K
JK
Thakur
Ganesh A
GA
Zvonok
Alexander M
AM
Hurst
Dow
D
Reggio
Patricia H
PH
Janero
David R
DR
Makriyannis
Alexandros
A
D000345:Affinity Labels / Q000378:metabolism; D000595:Amino Acid Sequence; D002460:Cell Line; D055808:Drug Discovery; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
D000345:Affinity Labels; D008024:Ligands; D050505:Mutant Proteins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2