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From the same journal

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

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Published copy (DOI)

Author(s)

  • Byron Carpenter
  • Glyn R Hemsworth
  • Zida Wu
  • Mabrouka Maamra
  • Christian J Strasburger
  • Richard J Ross
  • Peter J Artymiuk

Department/unit(s)

Publication details

JournalStructure
DatePublished - 7 Mar 2012
Issue number3
Volume20
Number of pages11
Pages (from-to)487-97
Original languageEnglish

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.

Bibliographical note

© 2012 Elsevier Ltd. All rights reserved.

    Research areas

  • Antibodies, Monoclonal, Binding Sites, Crystallography, X-Ray, Humans, Immunoglobulin Fab Fragments, Leptin, Models, Molecular, Protein Structure, Tertiary, Receptors, Leptin

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