Dopamine receptor microdomains involved in molecular recognition and the regulation of drug affinity and function

Christina Z. Floresca, John Schetz

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

A cationic protonatable amine moiety on dopaminergic ligands forms a high affinity reinforced ionic bond with an anionic aspartic acid at position 3.32 of dopamine receptors. When present, catechol hydroxyls of the ligands form hydrogen bonds with serines at position 5.42, 5.43, and 5.46, and this network of hydrogen bonds serves to orient ligands in the binding-site crevice and increase their binding affinity. A steric clash between aromatic moieties of the ligands and aromatic amino acids of the receptor (e.g., H6.55, F6.52 or F6.51 and W6.48) is likely to be propagated in domino-like fashion along the length of TM6, which is believed to trigger activation of the receptor. Specifically, it is the change in the conformation of W6.48 from an orientation perpendicular to the plane of the lipid membrane to one that is parallel that is believed to result in activation. Molecular determinants that mediate the D4/D2-selectivity of many extremely D4-selective 1,4-DAP ligands, include a nonconserved cluster of bulky amino acids at the TM2/TM3 interface (positions 2.61, 3.28 and 3.29).

Original languageEnglish
Pages (from-to)207-239
Number of pages33
JournalJournal of Receptors and Signal Transduction
Volume24
Issue number3
DOIs
StatePublished - 18 Oct 2004

Keywords

  • Antipsychotics
  • G protein-coupled receptors (GPCR)
  • Molecular recognition
  • Neurological disorders
  • Psychiatric disorders
  • Structure-activity relationships (SAR)
  • Structure-function
  • Subtype selective drugs

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