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

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

Zhou, Ye;Cao, Can;He, Lingli;Wang, Xianping;Zhang, Xuejun Cai;
eLife 2019 Vol. 8
357
zhou2019crystalelife

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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