A missense mutation in the seven-transmembrane domain of the human Ca 2+ receptor converts a negative allosteric modulator into a positive allosteric modulator

Jianxin Hu, Jiankang Jiang, Stefano Costanzi, Craig Thomas, Wu Yang, Jean H.M. Feyen, Kenneth A. Jacobson, Allen M. Spiegel

Research output: Contribution to journalArticle

38 Scopus citations


G protein-coupled receptors (GPCRs) are the most common targets of drug action. Allosteric modulators bind to the seven-transmembrane domain of family 3 GPCRs and offer enhanced selectivity over orthosteric ligands that bind to the large extracellular N terminus. We characterize a novel negative allosteric modulator of the human Ca2+ receptor, Compound 1, that retains activity against the E837A mutant that lacks a response to previously described positive and negative modulators. A related compound, JKJ05, acts as a negative allosteric modulator on the wild type receptor but as a positive modulator on the E837A mutant receptor. This positive modulation critically depends on the primary amine in JKJ05, which appears to interact with acidic residue Glu 767 in our model of the seven-transmembrane domain of the receptor. Our results suggest the need for identification of possible genetic variation in the allosteric site of therapeutically targeted GPCRs.

Original languageEnglish (US)
Pages (from-to)21558-21565
Number of pages8
JournalJournal of Biological Chemistry
Issue number30
StatePublished - Jul 28 2006
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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