TY - JOUR
T1 - Mutations of an antibody binding energy hot spot on domain III of the dengue 2 envelope glycoprotein exploited for neutralization escape
AU - Gromowski, Gregory D.
AU - Roehrig, John T.
AU - Diamond, Michael S.
AU - Lee, J. Ching
AU - Pitcher, Trevor J.
AU - Barrett, Alan D.T.
N1 - Funding Information:
This work was supported in part by the Pediatric Dengue Vaccine Initiative. GDG is supported by a NIAID T32 predoctoral fellowship ( AI060549 ). JCL is supported by the Robert A. Welch Foundation.
PY - 2010/11/25
Y1 - 2010/11/25
N2 - Previous crystallographic studies have identified a total of 11 DENV-2 envelope protein domain III (ED3) residues (K305, F306, K307, V308, V309, K310, I312, Q325, P364, K388, and N390) that interacted, through both side- and main-chain contacts, with the Fab of a dengue virus (DENV) subcomplex-specific neutralizing monoclonal antibody (MAb) 1A1D-2 (Lok et al., 2008). Here, we used DENV-2 recombinant ED3 mutants of the MAb 1A1D-2 structural epitope residues to determine the functional epitope of this MAb. The side-chains of residues K307, K310 and I312 were determined to be functionally critical for MAb binding, and thus constitute a hot spot of binding energy for MAb 1A1D-2 on the DENV-2 ED3. Overall, these findings demonstrate that only a subset of the amino acid residue side-chains within the structural epitope of MAb 1A1D-2 define a functional epitope on the DENV-2 ED3 that is essential for MAb binding and neutralization escape.
AB - Previous crystallographic studies have identified a total of 11 DENV-2 envelope protein domain III (ED3) residues (K305, F306, K307, V308, V309, K310, I312, Q325, P364, K388, and N390) that interacted, through both side- and main-chain contacts, with the Fab of a dengue virus (DENV) subcomplex-specific neutralizing monoclonal antibody (MAb) 1A1D-2 (Lok et al., 2008). Here, we used DENV-2 recombinant ED3 mutants of the MAb 1A1D-2 structural epitope residues to determine the functional epitope of this MAb. The side-chains of residues K307, K310 and I312 were determined to be functionally critical for MAb binding, and thus constitute a hot spot of binding energy for MAb 1A1D-2 on the DENV-2 ED3. Overall, these findings demonstrate that only a subset of the amino acid residue side-chains within the structural epitope of MAb 1A1D-2 define a functional epitope on the DENV-2 ED3 that is essential for MAb binding and neutralization escape.
KW - Dengue
KW - Envelope protein domain 3
KW - Monoclonal antibodies
KW - Neutralization
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U2 - 10.1016/j.virol.2010.06.044
DO - 10.1016/j.virol.2010.06.044
M3 - Article
C2 - 20832836
AN - SCOPUS:77957665570
SN - 0042-6822
VL - 407
SP - 237
EP - 246
JO - Virology
JF - Virology
IS - 2
ER -