6iql

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

Structural highlights

6iql is a 2 chain structure with sequence from Escherichia coli and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.5Å
Ligands:L74
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C562_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 PubMed

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.

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.

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See Also

References

  1. ↑ Hwang CK, Chaurasia SS, Jackson CR, Chan GC, Storm DR, Iuvone PM. Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. J Neurosci. 2013 Sep 18;33(38):14989-97. doi: 10.1523/JNEUROSCI.2039-13.2013. PMID:24048828 doi:http://dx.doi.org/10.1523/JNEUROSCI.2039-13.2013
  2. ↑ Zhou Y, Cao C, He L, Wang X, Zhang XC. Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870. Elife. 2019 Nov 21;8. pii: 48822. doi: 10.7554/eLife.48822. PMID:31750832 doi:http://dx.doi.org/10.7554/eLife.48822

Contents


PDB ID 6iql

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OCA

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