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Structure of the Human Obesity Receptor Leptin-Binding Domain Reveals the Mechanism of Leptin Antagonism by a Monoclonal Antibody
- Source :
-
Structure . Mar2012, Vol. 20 Issue 3, p487-497. 11p. - Publication Year :
- 2012
-
Abstract
- Summary: 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. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 09692126
- Volume :
- 20
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Structure
- Publication Type :
- Academic Journal
- Accession number :
- 73524752
- Full Text :
- https://doi.org/10.1016/j.str.2012.01.019