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Vol. 57, Issue 1, 171-179, January 2000

High-Affinity Binding of Peptide Agonists to the Human B1 Bradykinin Receptor Depends on Interaction between the Peptide N-Terminal L-Lysine and the Fourth Extracellular Domain of the Receptor

Dana B. Fathy, Donald J. Kyle, and L. M. Fredrik Leeb-Lundberg

Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas (D.B.F., L.M.F.L.-L.); and Department of Computational, Combinatorial, and Medicinal Chemistry, Purdue Pharma L.P., Ardsley, New York (D.J.K.)

The aim of this study was to identify the location of the N terminus of peptide agonist ligands when bound to the human B1 bradykinin (BK) receptor. To reach this aim, we exploited the fact that high-affinity binding of kinin peptides to the human B1 receptor subtype requires a peptide N-terminal L-Lys, whereas high-affinity binding to the B2 receptor subtype does not require this residue. This was done by comparing the affinities of BK, a B2 receptor-selective peptide, and kallidin or Lys-BK, a less receptor-selective peptide, for chimeric proteins in which each B1 receptor domain had been substituted in the human B2 receptor and expressed in HEK293 cells. Individual substitution of transmembrane domains 1-7 (TM-I-VII) and extracellular domains 1-4 (EC-I-IV) of the B1 receptor in the B2 receptor influenced the affinities of BK and Lys-BK approximately equally. In contrast, substitution of B1 EC-IV dramatically reduced the affinity and potency of BK, whereas these parameters for Lys-BK were essentially unaltered. Substitution of either the N- or C-terminal half of B1 EC-IV in the B2 receptor only had a limited effect on the peptide binding constants, indicating the involvement of multiple residues throughout this domain. Complementary mutations of the N-terminal residue in Lys-BK revealed that both the positive charge and the proper spatial orientation of this residue were required for interaction with B1 EC-IV. Thus, the N-terminal residue of peptide agonists when bound to the human B1 receptor is positioned extracellularly and interacts with EC-IV.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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