Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist

By E. Chien, Wei Liu, Qiang Zhao, Vsevolod Katritch, G. Han, M. Hanson, Lei Shi, A. Newman, J. Javitch, Vadim Cherezov and 1 more. 2010

1,139 citations recorded by the source corpus.

Tweaking Dopamine Reception Dopamine modulates many cognitive and emotional functions of the human brain by activating G protein–coupled receptors. Antipsychotic drugs that block two of the receptor subtypes are used to treat schizophrenia but have multiple side effects. Chien et al. (p. 1091; see the Research Article by Wu et al.) resolved the crystal structure of one receptor in complex with a small-molecule inhibitor at 3.15 angstrom resolution. Homology modeling with other receptor subtypes might be a promising route to reveal potential structural differences that can be exploited in the design of selective therapeutic inhibitors having fewer side effects. Discovery of a binding site in the extracellular domain of a dopamine receptor offers hope for more selective therapeutics. Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein–coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

Structure-based drug screening for G-protein-coupled receptors. (2012, background): “Since the initial crystal structures of the β2AR[11] and the β1AR[12], the number of published GPCRs which have yielded to crystallography has grown to ten and includes the adenosine A2A receptor[13], the D3 dopamine receptor[14], the CXCR4 receptor [15], the histamine H1 receptor, [16], the sphingo”
GPCR-I-TASSER: A hybrid approach to G protein-coupled receptor structure modeling and the application to the human genome (2015, methodology): “Left to right columns are models for CXCR4 chemokine receptor withIT1t(PDB:3oe6)(Wuetal.,2010),CXCRreceptorwithCVX15(PDB:3oe0) (Wu et al., 2010), and dopamine D 3 with eticlopride (PDB: 3pbl) (Chien et al., 2010),respectively.”
Structure-Function of the G-protein-Coupled Receptor Superfamily (2012, background): “Several potential allosteric sites in GPCRs revealed by crystal structures have been reviewed previously (53), including a phosphate ion binding site in the extracellular subpocket of the histamine H1 structure (28), a cholesterol binding site in β2AR (40) and a ‘druggable’ extracellular extension o”
A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets (2015, methodology): “Using the D3R-eticlopride cocrystal (13) as template, we created a D3R model lacking the D3 orthosteric antagonist eticlopride.”
Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor (2013, background): “Significant progress has been made through the development of GPCR fusion proteins, where a T4 lysozyme replaces the conformationally dynamic third intracellular loop (ICL3), for example (Cherezov et al., 2007; Jaakola et al., 2008; Chien et al., 2010; Wu et al., 2010; 2012; Shimamura et al., 2011; ”
New design strategies for antidepressant drugs (2013, background): “Crystal structures for the b1-adrenergic, DA D3, 5-HT1B and 5-HT2B receptors have been reported in the last 5 years [58-60].”
Lifting the lid on GPCRs: the role of extracellular loops (2011, background): “…can move between ordered and disordered conformations (analogous to the presence/absence of a 2.5 turn a-helix in ICL2 of D3R crystal structures; Chien et al., 2010), or it may represent a structural manifestation of the different receptor stabilization strategies employed for crystallization…”