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J. Biol. Chem., Vol. 281, Issue 15, 9841-9844, April 14, 2006

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A Low Molecular Weight Agonist Signals by Binding to the Transmembrane Domain of Thyroid-stimulating Hormone Receptor (TSHR) and Luteinizing Hormone/Chorionic Gonadotropin Receptor (LHCGR)^*

Holger Jäschke¹, Susanne Neumann¹, Susanna Moore, Craig J. Thomas^¶, Anny-Odile Colson^||, Stefano Costanzi^||, Gunnar Kleinau^||**, Jian-Kang Jiang^¶, Ralf Paschke, Bruce M. Raaka, Gerd Krause^**2, and Marvin C. Gershengorn³

From the Clinical Endocrinology Branch, ^¶Chemical Biology Laboratory, ^||Computational Chemistry Core Laboratory, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, ^**Leibniz-Institute of Molecular Pharmacology, 13125 Berlin, Germany, and III. Medical Department, University of Leipzig, 04103 Leipzig, Germany

Many cognate low molecular weight (LMW) agonists bind to seven transmembrane-spanning receptors within their transmembrane helices (TMHs). The thienopyrimidine org41841 was identified previously as an agonist for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and suggested to bind within its TMHs because it did not compete for LH binding to the LHCGR ectodomain. Because of its high homology with LHCGR, we predicted that thyroid-stimulating hormone receptor (TSHR) might be activated by org41841 also. We show that org41841 is a partial agonist for TSHR but with lower potency than for LHCGR. Analysis of three-dimensional molecular models of TSHR and LHCGR predicted a binding pocket for org41841 in common clefts between TMHs 3, 4, 5, 6, and 7 and extracellular loop 2 in both receptors. Evidence for this binding pocket was obtained in signaling studies with chimeric receptors that exhibited improved responses to org41841. Furthermore, a key receptor-ligand interaction between the highly conserved negatively charged E3.37 and the amino group of org41841 predicted by docking of the ligand into the three-dimensional TSHR model was experimentally confirmed. These findings provide the first evidence that, in contrast to the ectodomain binding of cognate ligands, a LMW agonist can bind to and activate glycoprotein hormone receptors via interaction with their transmembrane domain.

Received for publication, January 30, 2006 , and in revised form, February 13, 2006.

^* This work was supported by the Intramural Research Program of the NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Leibniz-Inst. of Molecular Pharmacology, Structural Bioinformatics and Protein Design, 13125 Berlin, Robert Roessle Strasse 10, Tel.: 49-30-94793228; Fax: 49-30-94793230; E-mail: GKrause{at}fmp-berlin.de. ³ To whom correspondence may be addressed: Scientific Director, NIDDK, National Institutes of Health, 50 South Dr., Bethesda, MD 20892-8029. Tel.: 301-451-6305; Fax: 301-480-4214; E-mail: marving{at}intra.niddk.nih.gov.

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