Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists.
We report the 3D structure of human beta2 adrenergic receptor (AR) predicted by using the MembStruk first principles method. To validate this structure, we use the HierDock first principles method to predict the ligand-binding sites for epinephrine and norepinephrine and for eight other ligands, including agonists and antagonists to beta 2 AR and ligands not observed to bind to beta 2 AR. The binding sites agree well with available mutagenesis data, and the calculated relative binding energies correlate reasonably with measured binding affinities. In addition, we find characteristic differences in the predicted binding sites of known agonists and antagonists that allow us to infer the likely activity of other ligands. The predicted ligand-binding properties validate the methods used to predict the 3D structure and function. This validation is a successful step toward applying these procedures to predict the 3D structures and function of the other eight subtypes of ARs, which should enable the development of subtype-specific antagonists and agonists with reduced side effects.
Freddolino
Lydia
L
Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA.
Kalani
M Yashar S
MY
Vaidehi
Nagarajan
N
Floriano
Wely B
WB
Hall
Spencer E
SE
Trabanino
Rene J
RJ
Kam
Victor Wai Tak
VW
Goddard
William A
WA
D000318:Adrenergic beta-Agonists / Q000737:chemistry*; D000319:Adrenergic beta-Antagonists / Q000737:chemistry*; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D004837:Epinephrine / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009638:Norepinephrine / Q000378:metabolism; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D009638:Norepinephrine; D004837:Epinephrine