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Crystal structure of dopamine receptor D4 bound to the subtype-selective ligand, L745870
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function.DRD4_MOUSE Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Activated by dopamine, but also by epinephrine and norepinephrine, and by numerous synthetic agonists and drugs. Agonist binding triggers signaling via G proteins that inhibit adenylyl cyclase (By similarity). Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells (PubMed:24048828).[UniProtKB:P21917][1] Publication Abstract from PubMedMultiple 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. Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870.,Zhou Y, Cao C, He L, Wang X, Zhang XC Elife. 2019 Nov 21;8. pii: 48822. doi: 10.7554/eLife.48822. PMID:31750832[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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