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Originally published In Press as doi:10.1074/jbc.M207420200 on November 21, 2002

J. Biol. Chem., Vol. 278, Issue 6, 4250-4257, February 7, 2003
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The Unique Ligand-binding Pocket for the Human Prostacyclin Receptor
SITE-DIRECTED MUTAGENESIS AND MOLECULAR MODELING*

Jeremiah Stitham, Aleksandar Stojanovic, Bethany L. Merenick, Kimberley A. O'Hara, and John HwaDagger

From the Department of Pharmacology & Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755

The human prostacyclin receptor is a seven-transmembrane alpha -helical G-protein coupled receptor, which plays important roles in both vascular smooth muscle relaxation as well as prevention of blood coagulation. The position of the native ligand-binding pocket for prostacyclin as well as other derivatives of the 20-carbon eicosanoid, arachidonic acid, has yet to be determined. Through the use of prostanoid receptor sequence alignments, site-directed mutagenesis, and the 2.8-Å x-ray crystallographic structure of bovine rhodopsin, we have developed a three-dimensional model of the agonist-binding pocket within the seven-transmembrane (TM) domains of the human prostacyclin receptor. Upon mutation to alanine, 11 of 29 candidate residues within TM domains II, III, IV, V, and VII exhibited a marked decrease in agonist binding. Of this group, four amino acids, Arg-279 (TMVII), Phe-278 (TMVII), Tyr-75 (TMII), and Phe-95 (TMIII), were identified (via receptor amino acid sequence alignment, ligand structural comparison, and computer-assisted homology modeling) as having direct molecular interactions with ligand side-chain constituents. This binding pocket is distinct from that of the biogenic amine receptors and rhodopsin where the native ligands (also composed of a carbon ring and a carbon chain) are accommodated in an opposing direction. These findings should assist in the development of novel and highly specific ligands including selective antagonists for further molecular pharmacogenetic studies of the human prostacyclin receptor.

* This work was supported by a start-up grant provided by the Department of Pharmacology & Toxicology and an American Heart Association Scientist Development Grant 0235260N.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology & Toxicology, 7650 Remsen, Dartmouth Medical School, Hanover, NH 03755. Tel.: 603-650-1813; Fax: 603-650-1129; E-mail: John.Hwa@Dartmouth.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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