| Abstract | Lymphocyte function-associated antigen 1 (LFA-1) plays important roles in immune cell adhesion, trafficking, and activation and is a therapeutic target for the treatment of multiple autoimmune diseases. Efalizumab is one of the most efficacious antibody drugs for treating psoriasis, a very common skin disease, through inhibition of the binding of LFA-1 to the ligand intercellular adhesion molecule 1 (ICAM-1). We report here the crystal structures of the Efalizumab Fab alone and in complex with the LFA-1 alpha(L) I domain, which reveal the molecular mechanism of inhibition of LFA-1 by Efalizumab. The Fab binds with an epitope on the inserted (I) domain that is distinct from the ligand-binding site. Efalizumab binding blocks the binding of LFA-1 to ICAM-1 via steric hindrance between its light chain and ICAM-1 domain 2 and thus inhibits the activities of LFA-1. These results have important implications for the development of improved antibodies and new therapeutic strategies for the treatment of autoimmune diseases. |
| Authors | Sheng Li, Hao Wang, Baozhen Peng, Meilan Zhang, Daipong Zhang, Sheng Hou, Yajun Guo, Jianping Ding
(Affiliation: State Key Laboratory of Molecular Biology and Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.)
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| Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 106
Issue 11
Pg. 4349-54
(Mar 17 2009)
ISSN: 1091-6490 [Electronic] United States |
| PMID | 19258452
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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| Chemical References |
- Antibodies, Monoclonal
- Epitopes
- Lymphocyte Function-Associated Antigen-1
- efalizumab
- Intercellular Adhesion Molecule-1
|
| Topics |
- Antibodies, Monoclonal
(pharmacology)
- Autoimmune Diseases
(drug therapy)
- Binding Sites
- Cell Migration Inhibition
(drug effects)
- Epitopes
- Humans
- Intercellular Adhesion Molecule-1
(metabolism)
- Lymphocyte Function-Associated Antigen-1
(metabolism)
- Protein Binding
(drug effects)
|
