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J. Biol. Chem., Vol. 282, Issue 19, 14253-14261, May 11, 2007

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NMR Structural Studies of Interactions of a Small, Nonpeptidyl Tpo Mimic with the Thrombopoietin Receptor Extracellular Juxtamembrane and Transmembrane Domains^*

Min-Ju Kim, Sang Ho Park, Stanley J. Opella, Thomas H. Marsilje, Pierre-Yves Michellys, H. Martin Seidel, and Shin-Shay Tian¹

From the Genomics Institute of the Novartis Research Foundation, San Diego, California, 92121 and Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0307

Thrombopoietin (Tpo) is a glycoprotein growth factor that supports hematopoietic stem cell survival and expansion and is the principal regulator of megakaryocyte growth and differentiation. Several small, nonpeptidyl molecules have been identified as selective human Tpo receptor (hTpoR) agonists. To understand how the small molecule Tpo mimic SB394725 interacts and activates hTpoR, we performed receptor domain swap and mutagenesis studies. The results suggest that SB394725 interacts specifically with the extracellular juxtamembrane region (JMR) and the transmembrane (TM) domain of hTpoR. Solution and solid-state NMR structural studies using a peptide containing the JMR-TM sequences showed that this region of hTpoR, unexpectedly, consists of two -helices separated by a few nonhelical residues. SB394725 interacts specifically with His-499 in the TM domain and a few distinct residues in the JMR-TM region and affects several specific C-terminal TM domain residues. The unique structural information provided by these studies both sheds light on the distinctive mechanism of action of SB394725 and provides valuable insight into the mechanism of ligand-induced cytokine receptor activation.

Received for publication, December 19, 2006 , and in revised form, February 23, 2007.

^* This research was supported by National Institutes of Health (NIH) Grant RO1GM066978 and utilized the Resource for NMR Molecular Imaging of Proteins supported by NIH Grant P41EB002031. 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.

¹ To whom correspondence should be addressed: Genomics Institute of Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, CA, 92121. Tel.: 858-332-4625; Fax: 858-812-1632; E-mail: stian{at}gnf.org.

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