한빛사 논문
Abstract
( alanine-scanning mutagenesis | crystal structure | humanized antibody | virus neutralization )
Seung-Wook Chi *, Cheol-Young Maeng , Seung Jun Kim *, Mee Sook Oh , Chun Jeih Ryu ¶, Sang Jick Kim , Kyou-Hoon Han , Hyo Jeong Hong ||, and Seong Eon Ryu *||
*Center for Cellular Switch Protein Structure, Molecular Cancer Research Center, Therapeutic Antibody Research Center, and Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Korea
Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved April 8, 2007 (received for review February 14, 2007)
The humanized monoclonal antibody HzKR127 recognizes the preS1 domain of the human hepatitis B virus surface proteins with a broadly neutralizing activity in vivo. We present the crystal structures of HzKR127 Fab and its complex with a major epitope peptide. In the complex structure, the bound peptide forms a type IV -turn followed by 310 helical turn, the looped-out conformation of which provides a structural basis for broad neutralization. Upon peptide binding, the antibody undergoes a dramatic complementarity determining region H3 lid opening. To understand the structural implication of the virus neutralization, we carried out comprehensive alanine-scanning mutagenesis of all complementarity determining region residues in HzKR127 Fab. The functional mapping of the antigen-combining site demonstrates the specific roles of major binding determinants in antigen binding, contributing to the rational design for maximal humanization and affinity maturation of the antibody.
Author contributions: S.-W.C. and C.-Y.M. contributed equally to this work; H.J.H. designed research; S.-W.C., C.-Y.M., Seung Jun Kim, M.S.O., C.J.R., Sang Jick Kim, and S.E.R. performed research; K.-H.H. and H.J.H. contributed new reagents/analytic tools; S.-W.C., C.-Y.M., Seung Jun Kim, M.S.O., C.J.R., Sang Jick Kim, K.-H.H., H.J.H., and S.E.R. analyzed data; and S.-W.C., H.J.H., and S.E.R. wrote the paper.
The authors declare no conflict of interest.
¶Present address: Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea.
||To whom correspondence may be addressed.
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