Solution structures in SDS micelles and functional activity at the bullfrog substance P receptor of ranatachykinin peptides

Shane A. Perrine, Tracy L. Whitehead, Rickey P. Hicks, John L. Szarek, James E. Krause, Mark A. Simmons

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A set of novel tachykinin-like peptides has been isolated from bullfrog brain and gut. These compounds, ranatachykinin A (RTKA), ranatachykinin B (RTKB), and ranatachykinin C (RTKC), were named for their source, Rana catesbeiana, and their homology to the tachykinin peptide family. We present the first report of the micelle-bound structures and pharmacological actions of the RTKs. Generation of three-dimensional structures of the RTKs in a membrane-model environment using 1H NMR chemical shift assignments, two- dimensional NMR techniques, and molecular dynamics and simulated annealing procedures allowed for the determination of possible prebinding ligand conformations. RTKA, RTKB, and RTKC were determined to be helical from the midregion to the C-terminus (residues 4-10), with a large degree of flexibility in the N-terminus and minor dynamic fraying at the end of the C- terminus. The pharmacological effects of the RTKs were studied by measuring the elevation of intracellular Ca2+ in Chinese hamster ovarian cells stably transfected with the bullfrog substance P receptor (bfSPR). All of the RTKs tested elicited Ca2+ elevations with a rank order of maximal effect of RTKA ≥ SP > RTKC ≥ RTKB. A high concentration (1/μM) of the neuropeptides produced varying degrees of desensitization to a subsequent challenge with the same or different peptide, while a low concentration (1 pM) produced sensitization at the bfSPR. Our data suggest differences in amino acid side chains and their charged states at the C-terminal sequence or differences in secondary structure at the N-terminus, which do not overlap according to the findings in this paper, may explain the differing degree and type of receptor activation seen at the bfSPR.

Original languageEnglish (US)
Pages (from-to)1741-1753
Number of pages13
JournalJournal of Medicinal Chemistry
Volume43
Issue number9
DOIs
StatePublished - May 30 2000

Fingerprint

Neurokinin-1 Receptors
Rana catesbeiana
Micelles
Peptides
Tachykinins
Pharmacology
Molecular Dynamics Simulation
Cricetulus
Neuropeptides
Ligands
Amino Acids
Membranes
Brain
ranatachykinin B
ranatachykinin C
ranatachykinin A

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Perrine, S. A., Whitehead, T. L., Hicks, R. P., Szarek, J. L., Krause, J. E., & Simmons, M. A. (2000). Solution structures in SDS micelles and functional activity at the bullfrog substance P receptor of ranatachykinin peptides. Journal of Medicinal Chemistry, 43(9), 1741-1753. https://doi.org/10.1021/jm000093v

Solution structures in SDS micelles and functional activity at the bullfrog substance P receptor of ranatachykinin peptides. / Perrine, Shane A.; Whitehead, Tracy L.; Hicks, Rickey P.; Szarek, John L.; Krause, James E.; Simmons, Mark A.

In: Journal of Medicinal Chemistry, Vol. 43, No. 9, 30.05.2000, p. 1741-1753.

Research output: Contribution to journalArticle

Perrine, Shane A. ; Whitehead, Tracy L. ; Hicks, Rickey P. ; Szarek, John L. ; Krause, James E. ; Simmons, Mark A. / Solution structures in SDS micelles and functional activity at the bullfrog substance P receptor of ranatachykinin peptides. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 9. pp. 1741-1753.
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