2. Academic Validation
  3. Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody

Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody

  • Structure. 2012 Mar 7;20(3):487-97. doi: 10.1016/j.str.2012.01.019.
Byron Carpenter 1,  Glyn R Hemsworth,  Zida Wu,  Mabrouka Maamra,  Christian J Strasburger,  Richard J Ross,  Peter J Artymiuk
Affiliations

Affiliation

  • 1 Academic Unit of Diabetes, Endocrinology and Reproduction, Department of Human Metabolism, University of Sheffield, Sheffield S10 2JF, UK.
PMID: 22405007 DOI: 10.1016/j.str.2012.01.019
Abstract

Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR. We describe the structure of the LBD-9F8 Fab complex and the conformational changes in 9F8 associated with LBD binding. A molecular model of the putative leptin-LBD complex reveals that 9F8 Fab blocks Leptin binding through only a small (10%) overlap in their binding sites, and that Leptin binding is likely to involve an induced fit mechanism. This crystal structure of the leptin-binding domain of the obesity receptor will facilitate the design of therapeutics to modulate Leptin signaling.

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