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

Elife. 2019 Nov 21;8:e48822. doi: 10.7554/eLife.48822.

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.

Keywords: DRD4; GPCR; antagonist; dimerization; ligand binding; molecular biophysics; mouse; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Dopamine / chemistry*
  • Dopamine / metabolism
  • Humans
  • Ligands
  • Mice
  • Molecular Dynamics Simulation
  • Protein Binding / drug effects
  • Protein Conformation, alpha-Helical / drug effects*
  • Protein Structure, Secondary
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Receptors, Dopamine D4 / antagonists & inhibitors
  • Receptors, Dopamine D4 / chemistry*
  • Structure-Activity Relationship

Substances

  • 3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
  • Drd4 protein, mouse
  • Ligands
  • Pyridines
  • Pyrroles
  • Receptors, Dopamine D4
  • Dopamine

Associated data

  • PDB/6IQL