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J. Biol. Chem., Vol. 279, Issue 39, 41038-41046, September 24, 2004

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Mapping of the Leptin Binding Sites and Design of a Leptin Antagonist^*

Frank Peelman, Katrien Van Beneden, Lennart Zabeau, Hannes Iserentant, Peter Ulrichts, Delphine Defeau, Annick Verhee, Dominiek Catteeuw, Dirk Elewaut, and Jan Tavernier¶

From the Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Interuniversity Institute for Biotechnology, VIB09, Ghent University, Albert Baertsoenkaai 3 and the Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium

The leptin/leptin receptor system shows strong similarities to the long-chain cytokine interleukin-6 (IL-6) and granulocyte colony-stimulating factor cytokine/receptor systems. The IL-6 family cytokines interact with their receptors through three different binding sites I-III. The leptin structure was superposed on the crystal structures of several long-chain cytokines, and a series of leptin mutants was generated focusing on binding sites I-III. The effect of the mutations on leptin receptor (LR) signaling and on binding to the membrane proximal cytokine receptor homology domain (CRH2) of the LR was determined. Mutations in binding site I at the C terminus of helix D show a modest effect on signaling and do not affect binding to CRH2. Binding site II is composed of residues at the surface of helices A and C. Mutations in this site impair binding to CRH2 but have only limited effect on signaling. Site III mutations around the N terminus of helix D impair receptor activation without affecting binding to CRH2. We identified an S120A/T121A mutant in binding site III, which lacks any signaling capacity, but which still binds to CRH2 with wild type affinity. This leptin mutant behaves as a potent leptin antagonist both in vitro and in vivo.

Received for publication, May 4, 2004 , and in revised form, June 17, 2004.

^* This work was supported by a grant (to F. P.) from the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie, and by the Fonds voor Wetenschappelijk Onderzoek (Grant G.0071.03). 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.

^¶ 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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