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

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.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC6872212 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Zhou Ye Y Cao Can C He Lingli L Wang Xianping X Zhang Xuejun Cai XC

eLife 20191121

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 orthos ...[more]

PMID: 31750832

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