QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.035535v1 72/2/238    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Related articles in MolPharm Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kohout, T. A. Articles by Struthers, R. S. Search for Related Content PubMed PubMed Citation Articles by Kohout, T. A. Articles by Struthers, R. S.

Trapping of a Nonpeptide Ligand by the Extracellular Domains of the Gonadotropin-Releasing Hormone Receptor Results in Insurmountable Antagonism

Departments of Endocrinology (T.A.K., Q.X., S.R., K.J.F., R.S.S.) and Medicinal Chemistry (Z.G., Y.-F.Z.), Neurocrine Biosciences Inc., San Diego, California

Drugs that exhibit insurmountable antagonism are proposed to provide improved clinical efficacy through extended receptor blockade. Long-term suppression of the gonadotropin-releasing hormone receptor (GnRHR) is an important therapeutic approach for a number of sex hormone-dependent diseases. In this study, we describe the mechanism and structural components required for insurmountable activity of a GnRHR antagonist. TAK-013 behaves as an insurmountable antagonist at the human receptor (hGnRHR) but as a surmountable antagonist at the macaque receptor (mGnRHR). Mutation of the eight residues that differ between hGnRHR and mGnRHR identified Ser-203 and Leu-300 in extracellular loops (ECL) 2 and 3 of hGnRHR as essential for the insurmountability of TAK-013. Substitution of the corresponding residues in mGnRHR with Ser and Leu (mGnRHR-P203S/V300L) converts TAK-013 to an insurmountable antagonist. In addition, mutation of Met-24 to Leu in the amino terminus of hGnRHR also ablates the insurmountable antagonism of TAK-013. The mechanism of insurmountability of TAK-013 was determined to be governed by its rate of dissociation from the receptor. Although the association rates of TAK-013 to hGnRHR, mGnRHR, and mGnRHR-P203S/V300L do not differ, the dissociation rate half-life correlates closely with the degree of insurmountability observed (169, 9, and 55 min, respectively). Taken together, these data suggest a model of the GnRHR in which ECL2, ECL3, and the amino terminus engage with TAK-013 upon its binding to the transmembrane region of the receptor. These additional interactions form a "trap door" above TAK-013, restricting its dissociation and thus resulting in its insurmountability.

Address correspondence to: Trudy A. Kohout, Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130. E-mail: tkohout{at}neurocrine.com

Related articles in MolPharm:

Challenges and Opportunities of Trapping Ligands

Mariusz W. Szkudlinski
MolPharm 2007 72: 231-234. [Abstract] [Full Text]  

This article has been cited by other articles:

				M. W. Szkudlinski Challenges and Opportunities of Trapping Ligands Mol. Pharmacol., August 1, 2007; 72(2): 231 - 234. [Abstract] [Full Text] [PDF]