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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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Received 2019-05-27, accepted for publication 2019-11-06, Published 2019-11-06

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.


Mouse;dimerization;DRD4;antagonist;ligand binding;GPCR


© 2019, Zhou et al
http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


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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