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

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2019
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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.
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zhou2019crystalelife Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Zhou, Ye;Cao, Can;He, Lingli;Wang, Xianping;Zhang, Xuejun Cai;
Journal eLife
Year 2019
DOI
10.7554/eLife.48822
URL
Keywords
gpcr mouse molecular biophysics structural biology ligand binding dimerization antagonist drd4

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