Mutations in the B 2 Bradykinin Receptor Reveal a Different Pattern of Contacts for Peptidic Agonists and Peptidic Antagonists *
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 271, Issue: 45, Page: 28277-28286
1996
- 67Citations
- 7Captures
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Metrics Details
- Citations67
- Citation Indexes67
- 67
- CrossRef56
- Captures7
- Readers7
Article Description
The B 2 bradykinin receptor, a seven-helix transmembrane receptor, binds the inflammatory mediator bradykinin (BK) and the structurally related peptide antagonist HOE-140. The binding of HOE-140 and the binding of bradykinin are mutually exclusive and competitive. Fifty-four site-specific receptor mutations were made. BK's affinity is reduced 2200-fold by F261A, 490-fold by T265A, 60-fold by D286A, and 3-10-fold by N200A, D268A, and Q290A. In contrast, HOE-140 affinity is reduced less than 7-fold by F254A, F261A, Y297A, and Q262A. The almost complete discordance of mutations that affect BK binding versus HOE-140 binding is surprising, but it was paralleled by the effect of single changes in BK and HOE-140. [Ala 9 ]BK and [Ala 6 ]BK are reduced in receptor binding affinity 27,000- and 150-fold, respectively, while [Ala 9 ]HOE-140 affinity is reduced 7-fold and [Ala 6 ]HOE-140 affinity is unchanged. NMR spectroscopy of all of the peptidic analogs of BK or HOE-140 revealed a β-turn at the C terminus. Models of the receptor-ligand complex suggested that bradykinin is bound partially inside the helical bundle of the receptor with the amino terminus emerging from the extracellular side of helical bundle. In these models a salt bridge occurs between Arg 9 and Asp 286 ; the models also place Phe 8 in a hydrophobic pocket midway through the transmembrane region. Models of HOE-140 binding to the receptor place its β-turn one α-helical turn deeper and closer to helix 7 and helix 1 as compared with bradykinin-receptor complex models.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925818351433; http://dx.doi.org/10.1074/jbc.271.45.28277; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=10344255641&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/8910447; https://linkinghub.elsevier.com/retrieve/pii/S0021925818351433; https://dx.doi.org/10.1074/jbc.271.45.28277
Elsevier BV
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