Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization. / Kim, Mikyung; Sun, Zhen-Yu J; Rand, Kasper Dyrberg; Shi, Xiaomeng; Song, Likai; Cheng, Yuxing; Fahmy, Amr F; Majumdar, Shreoshi; Ofek, Gilad; Yang, Yongping; Kwong, Peter D; Wang, Jia-Huai; Engen, John R; Wagner, Gerhard; Reinherz, Ellis L.
In: Nature Structural and Molecular Biology, Vol. 18, No. 11, 2011, p. 1235-43.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization
AU - Kim, Mikyung
AU - Sun, Zhen-Yu J
AU - Rand, Kasper Dyrberg
AU - Shi, Xiaomeng
AU - Song, Likai
AU - Cheng, Yuxing
AU - Fahmy, Amr F
AU - Majumdar, Shreoshi
AU - Ofek, Gilad
AU - Yang, Yongping
AU - Kwong, Peter D
AU - Wang, Jia-Huai
AU - Engen, John R
AU - Wagner, Gerhard
AU - Reinherz, Ellis L
PY - 2011
Y1 - 2011
N2 - Broadly neutralizing antibodies such as 2F5 are directed against the membrane-proximal external region (MPER) of HIV-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 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.
AB - Broadly neutralizing antibodies such as 2F5 are directed against the membrane-proximal external region (MPER) of HIV-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 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.
U2 - 10.1038/nsmb.2154
DO - 10.1038/nsmb.2154
M3 - Journal article
C2 - 22002224
VL - 18
SP - 1235
EP - 1243
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 11
ER -
ID: 40129348