Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Abstract

Summary Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases ranging from schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, nausea and vomiting, among others. Dopamine’s actions are mediated by a family of five G-protein coupled receptors (GPCRs) (viz. D1, D2, D3, D4 and D5)1. The D2 dopamine receptor (DRD2) is the primary target for both typical2 and atypical3,4 antipsychotic drugs, and for Parkinson’s disease drugs. Unfortunately, many drugs targeting DRD2 frequently suffer from serious and potentially life-threatening side effects due to promiscuous activities against related receptors4,5. Accordingly, a molecular understanding of DRD2 structure and function could provide a template for the design of safer and more effective medications. Here we provide the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and illuminates structural determinants essential for the actions of risperidone and related drugs at DRD2.

Distinct antagonist-bound inactive states underlie the divergence in the structures of the dopamine D2 and D3 receptors

“…Thus, we infer that the distinct conformation of Trp100 EL1.50 in the D2R structure is a combined effect of the helical EL2 conformation and the favored interaction that Trp100 EL1.50 can form with bound risperidone in the crystal structure, the latter of which however, has a minimal influence on the binding affinity of risperidone 10 , consistent with the unstable interaction between risperidone and Trp100 EL1.50 in our simulations ( Fig. 4, Supplementary Movie 2).…”

“…This is consistent with our simulation results that show the I122 3.40 A mutation has minimal impact on risperidone binding. Both Ile122 3.40 and Phe382 6.44 of the Ile122 3.40 sub-pocket are part of the conserved Pro 5.50 -Ile 3.40 -Phe 6.44 motif that undergoes rearrangement upon receptor activation 17 , and we have found that the I122A mutation renders the receptor non-functional 10,18 . Thus, the I122A mutation may promote an inactive conformation of D2R that favors eticlopride binding but has no effect on the binding of risperidone or spiperone.…”

“…Curiously, the structures of the highly homologous dopamine D2 and D3 receptors (D2R and D3R) in the inactive states revealed quite substantial differences on the extracellular side of the transmembrane domain when bound with antagonists from different scaffolds 9,10 . Specifically, the D3R structure is in complex with eticlopride, a substituted benzamide (PDB: 3PBL) 9 , while the D2R structure is bound with risperidone, a benzisoxazole derivative (PDB: 6CM4) 10 . The binding poses of the two ligands differ substantially.…”

“…The binding poses of the two ligands differ substantially. The risperidone is oriented relatively perpendicular to the membrane plane with its benzisoxazole ring penetrating into a hydrophobic pocket beneath the orthosteric binding site (OBS) of D2R; in contrast, eticlopride is oriented relatively parallel to the 4 membrane plane contacting the extracellular portion of TM5 in D3R that risperidone does not touch in D2R 10,11 . Nemonapride, another substituted benzamide, binds in the OBS of the slightly divergent D4R (PDB: 5WIV) 12 in a manner very similar to that of eticlopride in the D3R 11 .…”

Highly Sensitive and Selective Electrochemical Detection of Dopamine using Hybrid Bilayer Membranes

“…Dopamine (DA), a typical neurotransmitter, plays a critical role in the central nervous systems to control reward-related behaviors, movement initiation, release of hormones, etc. [1][2][3] An abnormal level of DA can lead to severe diseases, such as Parkinson's, [4] schizophrenia, [5] and depression. [6] The reliable and accurate detection of DA, however, is not easy.…”