한빛사논문
- 조회2,274
Harvard Medical School
Abstract
Mikyung Kim1,2, Zhen-Yu J Sun3, Kasper D Rand4, Xiaomeng Shi4, Likai Song2,5,6, Yuxing Cheng1,7, Amr F Fahmy3, Shreoshi Majumdar1, Gilad Ofek8, Yongping Yang8, Peter D Kwong8, Jia-Huai Wang1,9, John R Engen4, Gerhard Wagner3 & Ellis L Reinherz1,2,5
1Laboratory of Immunobiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. 4Department of Chemistry & Chemical Biology and The Barnett Institute of Chemical & Biological Analysis, Northeastern University, Boston, Massachusetts, USA. 5Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 6National High Magnetic Field Laboratory, Tallahassee, Florida, USA. 7PhD Program in Biological Sciences in Public Health, Harvard School of Public Health, Boston, Massachusetts, USA. 8Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 9Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. Correspondence should be addressed to E.L.R.
Broadly neutralizing antibodies such as 2F5 are directed against the membrane-proximal external region (MPER) of HIV-1 1 GP41 and recognize well-defined linear core sequences. These epitopes can be engrafted onto protein scaffolds to serve as immunogens with high structural fidelity. Although antibodies that bind to this core GP41 1 epitope can be elicited, they lack neutralizing activity. To understand this paradox, we used biophysical methods to investigate the binding of human 2F5 to the MPER in a membrane environment, where it resides in vivo. Recognition is stepwise, through a paratope more extensive than core binding site contacts alone, and dynamic rearrangement through an apparent scoop-like movement of heavy chain complementarity-determining region 3 (CDRH3) is essential for MPER extraction from the viral membrane. Core-epitope recognition on the virus requires the induction of conformational changes in both the MPER and the paratope. Hence, target neutralization through this lipid-embedded viral segment places stringent requirements on the plasticity of the antibody combining site.
논문정보
- Research article
- 2011년 10월 (BRIC 등록일 )
- 국외 연구진
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