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Elife. 2019 Nov 21;8. pii: e48822. doi: 10.7554/eLife.48822.

Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870.

Author information

1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
2
University of Chinese Academy of Sciences, Beijing, China.

Abstract

Multiple subtypes of dopamine receptors within the GPCR superfamily regulate neurological processes through various downstream signaling pathways. A crucial question about the dopamine receptor family is what structural features determine the subtype-selectivity of potential drugs. Here, we report the 3.5-angstrom crystal structure of mouse dopamine receptor D4 (DRD4) complexed with a subtype-selective antagonist, L745870. Our structure reveals a secondary binding pocket extended from the orthosteric ligand-binding pocket to a DRD4-specific crevice located between transmembrane helices 2 and 3. Additional mutagenesis studies suggest that the antagonist L745870 prevents DRD4 activation by blocking the relative movement between transmembrane helices 2 and 3. These results expand our knowledge of the molecular basis for the physiological functions of DRD4 and assist new drug design.

KEYWORDS:

DRD4; GPCR; antagonist; dimerization; ligand binding; molecular biophysics; mouse; structural biology

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