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Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody
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Carpenter, Byron, Hemsworth, Glyn R., Wu, Zida, Maamra, Mabrouka, Strasburger, Christian J., Ross, Richard J. and Artymiuk, Peter J. (2012) Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody. Structure, 20 (3). pp. 487-497. doi:10.1016/j.str.2012.01.019 ISSN 0969-2126.
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Official URL: http://dx.doi.org/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.
| Item Type: | Journal Article | ||||||||
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
| Journal or Publication Title: | Structure | ||||||||
| Publisher: | Cell Press | ||||||||
| ISSN: | 0969-2126 | ||||||||
| Official Date: | 6 March 2012 | ||||||||
| Dates: |
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| Volume: | 20 | ||||||||
| Number: | 3 | ||||||||
| Page Range: | pp. 487-497 | ||||||||
| DOI: | 10.1016/j.str.2012.01.019 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||
| Adapted As: |
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