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The amino-terminus of angiotensin II contacts several ectodomains of the angiotensin II receptor AT1.

Abstract：

:G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and major targets for drug development. Herein, we sought to identify the regions of the human angiotensin II (AngII) type 1 (hAT(1)) receptor binding cleft that interact with all positions of the AngII using photoaffinity labeling. We conducted a complete iterative walk-through of the AngII sequence with either p-benzoyl-L-phenylalanine (Bpa) or p-[3-(trifluoromethyl)-3H-diazirin-3-yl]-L-phenylalanine (Tdf) to yield two series of eight photoreactive analogues. Pharmacological properties assessment of these sixteen analogues showed that the CAM receptor has a structure-activity relationship (SAR) more amenable to the amino acid substitutions at positions 1, 2, 3, and 5 of AngII than the WT receptor. Photoaffinity labeling of the CAM receptor with the selected analogues, which exhibit different but complementary photochemical properties, suggested that the AngII amino-terminus resides in a hydrophilic environment and interacts simultaneously with different regions of the hAT(1) receptor, including several ectodomains.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Fillion D,Lemieux G,Basambombo LL,Lavigne P,Guillemette G,Leduc R,Escher E

doi

10.1021/jm9015747

subject

Has Abstract

pub_date

2010-03-11 00:00:00

pages

2063-75

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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