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J. Biol. Chem., Vol. 281, Issue 22, 15496-15504, June 2, 2006

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Mapping of Binding Site III in the Leptin Receptor and Modeling of a Hexameric Leptin·Leptin Receptor Complex^*

From the Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology, and the Faculty of Medicine and Health Sciences, Ghent University, Baertsoenkaai 3, 9000 Ghent, Belgium

The leptin·leptin receptor (LR) system shows strong similarities to the long chain cytokine interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) cytokine·cytokine receptor systems. The IL-6 family cytokines interact with their receptors through three different binding sites (I–III). We demonstrated previously that leptin has similar binding sites I–III and mapped the interactions between binding site II and cytokine receptor homology domain II (CRH2) (Peelman, F., Van Beneden, K., Zabeau, L., Iserentant, H., Ulrichts, P., Defeau, D., Verhee, A., Catteeuw, D., Elewaut, D., and Tavernier, J. (2004) J. Biol. Chem. 279, 41038–41046). In this study, we built homology models for the CRH1 and Ig-like domains of the LR. The Ig-like domain shows a large conserved surface patch in the -sheet formed by -strands 3, 6, and 7. Mutations in this patch almost completely abolished the leptin-induced STAT3-dependent reporter activity. We propose that a conserved cluster of residues Leu³⁷⁰, Ala⁴⁰⁷, Tyr⁴⁰⁹, His⁴¹⁷, and His⁴¹⁸ forms the center of binding site III of the LR. We built a hexameric leptin·LR complex model based on the hexameric IL-6 complex. In this model, a conserved hydrophobic protuberance of Val³⁶, Thr³⁷, Phe⁴¹, and Phe⁴³ in the A–B loop of leptin fits perfectly in the CRH2 domain, corresponding to the IL-6 -receptor, and forms the center of binding site I. The 2:4 hexameric leptin·LR complex offers a rational explanation for mutagenesis studies and residue conservation.

Received for publication, November 28, 2005 , and in revised form, January 31, 2006.

^* This work was supported by Institute for the Promotion of Innovation by Science and Technology in Flanders (IWF) grants from the Flanders Institute of Science and Technology (to F. P.) and by Grant 1.5.446.98 [EC] from the Fund for Scientific Research of Flanders (to H. I. and L. Z.). 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 a supplemental table.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 32-9-264-9302; Fax: 32-9–264-9492; E-mail: jan.tavernier{at}ugent.be.

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