Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes.
Focusing on the similarity and divergence of GPCR subtypes and their ligand interactions, we generated dopamine D2, D3, and D4 receptor models based on the rhodopsin crystal structure and refined these with an extensive MM/MD protocol. After validation by diagnostic experimental data, subtype-specific relative positions of TM1, 2, 6, and 7 and bending angles of TM7 were found. To sample the conformational space of the complex, we performed simulated-annealing runs of the receptor protein with the sub-nanomolar antagonist spiperone. Docking a representative set of ligands, we were able to identify one superior model for each subtype when excellent correlations between predicted energies of binding and experimental affinities (r2 = 0.72 for D2, 0.91 for D3 and 0.77 for D4) could be observed. Further analysis revealed general ligand interactions with ASP3.32 and aromatic residues in TM6/7 and individual key interactions with TM1 and TM2 residues of the D3 and D4 receptor models, respectively.
Boeckler
Frank
F
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Lanig
Harald
H
Gmeiner
Peter
P
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D017124:Conserved Sequence; D018492:Dopamine Antagonists / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000235:genetics; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D013134:Spiperone / Q000737:chemistry
C493593:DRD3 protein, human; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D013134:Spiperone; D012243:Rhodopsin