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Research ArticleArticle

Structural Determinants Required for the Bioactivities of Prokineticins and Identification of Prokineticin Receptor Antagonists

Clayton M. Bullock, Jia-Da Li and Qun-Yong Zhou
Molecular Pharmacology March 2004, 65 (3) 582-588; DOI: https://doi.org/10.1124/mol.65.3.582
Clayton M. Bullock
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Jia-Da Li
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Qun-Yong Zhou
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Abstract

Prokineticins are cysteine-rich secreted proteins that regulate diverse biological processes, including gastrointestinal motility, angiogenesis, and circadian rhythms. Two closely related G protein-coupled receptors that mediate signal transduction of prokineticins have recently been cloned. The structural elements required for prokineticins' bioactivities are still unknown. We show here that both the N-terminal hexapeptide (AVITGA) and C-terminal cysteine-rich domains are critical for the bioactivities of prokineticins. Substitutions, deletions, and insertions to the conserved N-terminal hexapeptides result in the loss of agonist activity. Mutant prokineticins with the substitution of the first N-terminal alanine with methionine or the addition of a methionine to the N terminus inhibit the activation of prokineticin receptors and thus are considered as antagonists of prokineticin receptors. We have further shown that mutations in selected cysteine residues in the C-terminal domain result in prokineticins without biological activity. The essential role of C-terminal domain is reinforced by two observations: that peptides without the carboxyl domain and proteins with the N-terminal hexapeptide fused to the carboxyl domains of colipase or dickkopf are devoid of biological activity. We demonstrate that limited structural changes of C-terminal cysteine-rich regions of prokineticins are tolerable because chimeric prokineticins with swapped cysteine-rich domains between prokineticin 1 and prokineticin 2, as well as a splice variant of prokineticin 2 that contains extra 21 residue insertion in its C-terminal domain, are biologically active.

  • Received June 19, 2003.
  • Accepted November 13, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (3)
Molecular Pharmacology
Vol. 65, Issue 3
1 Mar 2004
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Research ArticleArticle

Structural Determinants Required for the Bioactivities of Prokineticins and Identification of Prokineticin Receptor Antagonists

Clayton M. Bullock, Jia-Da Li and Qun-Yong Zhou
Molecular Pharmacology March 1, 2004, 65 (3) 582-588; DOI: https://doi.org/10.1124/mol.65.3.582

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Research ArticleArticle

Structural Determinants Required for the Bioactivities of Prokineticins and Identification of Prokineticin Receptor Antagonists

Clayton M. Bullock, Jia-Da Li and Qun-Yong Zhou
Molecular Pharmacology March 1, 2004, 65 (3) 582-588; DOI: https://doi.org/10.1124/mol.65.3.582
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