G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations.
A 5-HT(2A) receptor model was constructed by homology modeling based on the β(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(αq) peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT(2A) receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
Vignir
V
Isberg
Thomas
T
Balle
Tommy
T
Sander
Flemming Steen
FS
Jørgensen
David E
DE
Gloriam
D001665:Binding Sites; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D005110:Extracellular Space / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D055355:Opsins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015203:Reproducibility of Results; D058826:Serotonin 5-HT2 Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology; D014584:User-Computer Interface
D055355:Opsins; D010446:Peptide Fragments; D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A; D018343:Receptors, Adrenergic, beta-2; D058826:Serotonin 5-HT2 Receptor Agonists; D043802:GTP-Binding Protein alpha Subunits, Gq-G11