title: Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody.
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.
authors.affiliation: Academic Unit of Diabetes, Endocrinology and Reproduction, Department of Human Metabolism, University of Sheffield, Sheffield S10 2JF, UK.
authors.forename: Byron
authors.initials: B
authors.lastname: Carpenter
authors.forename: Glyn R
authors.initials: GR
authors.lastname: Hemsworth
authors.forename: Zida
authors.initials: Z
authors.lastname: Wu
authors.forename: Mabrouka
authors.initials: M
authors.lastname: Maamra
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Strasburger
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Artymiuk
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D054411:Receptors, Leptin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; C515448:LEPR protein, human; D020738:Leptin; D054411:Receptors, Leptin