
eLife | Volume 8 ,2019-11-06 |
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 | |
Structural Biology and Molecular Biophysics | |
Ye Zhou 1 , 2 Can Cao 1 Lingli He 1 Xianping Wang 1 Xuejun Cai Zhang 1 , 2 | |
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DOI:10.7554/eLife.48822 | |
Received 2019-05-27, accepted for publication 2019-11-06, Published 2019-11-06 | |
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摘要
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.
关键词
Mouse;dimerization;DRD4;antagonist;ligand binding;GPCR
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Ye Zhou,Can Cao,Lingli He,Xianping Wang,Xuejun Cai Zhang. Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870. eLife ,Vol.8(2019)
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