Journal Article

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

Che, Tao, Wacker, Daniel, Levit, Anat, Roth, Bryan L., Shoichet, Brian K., Wang, Sheng

2018

Overview

An X-ray structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone reveals an extended binding pocket and indicates structural features that could be used to design drugs that specifically target the D2 receptor. Dopamine's unusual binding technique D2 dopamine receptors are the principal targets for antipsychotic drugs for the treatment of schizophrenia, and offer possibilities for treating depression and Parkinson's disease. However, molecular-level understanding of these receptors is limited, and many available drugs cause serious side-effects as a result of activity at other dopamine receptors. Here, Bryan Roth and colleagues report the crystal structure of the D2 receptor in complex with the antipsychotic drug risperidone. This structure shows an unusual binding mode of the drug, distinct from those observed in the related D3 and D4 receptors, whereby a hydrophobic patch formed by a tryptophan residue regulates the entry and exit of the drug. Mutation at this position reduces the drug residence time, which is believed to be related to side-effects of common antipsychotics. This work hints at ways to develop safer antipsychotic drugs that are selective for D2. 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 such as schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors 1 . The D2 dopamine receptor (DRD2) is the primary target for both typical 2 and atypical 3 , 4 antipsychotic drugs, and for drugs used to treat Parkinson’s disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors 4 , 5 . Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report 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 highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/535/1266 / 631/92/436/2387 / 82/80 / 82/83 / 96/95 / Addictions / Antipsychotic Agents - chemistry / Antipsychotic Agents - metabolism / Antipsychotics / Attention deficit hyperactivity disorder / Binding Sites / Crystal structure / Crystallography, X-Ray / Dopamine / Dopamine D2 receptors / Dopamine receptors / Drug Design / Drug interactions / Drugs / Humanities and Social Sciences / Humans / Hydrophobic and Hydrophilic Interactions / Kinetics / letter / Ligands / Mental depression / Mental disorders / Metabolism / Models, Molecular / Molecular structure / Movement disorders / multidisciplinary / Mutant Proteins - chemistry / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Nausea / Neurodegenerative diseases / Parkinson's disease / Pharmacological research / Physiological aspects / Proteins / Psychotropic drugs / Receptors / Receptors, Dopamine D2 - chemistry / Receptors, Dopamine D2 - genetics / Receptors, Dopamine D2 - metabolism / Receptors, Dopamine D3 - chemistry / Receptors, Dopamine D3 - metabolism / Receptors, Dopamine D4 - chemistry / Receptors, Dopamine D4 - metabolism / Reinforcement / Risperidone / Risperidone - chemistry / Risperidone - metabolism / Schizophrenia / Science / Secretion / Side effects / Structure / Structure-function relationships / Vomiting