Antigen clasping by two antigen-binding sites of an exceptionally specific antibody for histone methylation
| Autor: | Neil L. Kelleher, Takamitsu Hattori, Kohei Kurosawa, Irina Dementieva, Brian D. Strahl, Darson Lai, Alexander J. Ruthenburg, Sherwin P. Montaño, Kalina M. Świst-Rosowska, Akiko Koide, Krzysztof Krajewski, Shohei Koide, Adrian T. Grzybowski, Louesa R. Akin, Yupeng Zheng |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Multidisciplinary biology Antibodies Monoclonal Biological Sciences Crystallography X-Ray Methylation Fragment crystallizable region Histones Immunoglobulin Fab Fragments 03 medical and health sciences Histone H3 030104 developmental biology Histone Molecular recognition Biochemistry Antigen Histone methylation biology.protein Humans Binding Sites Antibody Antigens Antibody Protein Structure Quaternary Linker |
| DOI: | 10.17615/23g9-an88 |
| Popis: | Antibodies have a well-established modular architecture wherein the antigen-binding site residing in the antigen-binding fragment (Fab or Fv) is an autonomous and complete unit for antigen recognition. Here, we describe antibodies departing from this paradigm. We developed recombinant antibodies to trimethylated lysine residues on histone H3, important epigenetic marks and challenging targets for molecular recognition. Quantitative characterization demonstrated their exquisite specificity and high affinity, and they performed well in common epigenetics applications. Surprisingly, crystal structures and biophysical analyses revealed that two antigen-binding sites of these antibodies form a head-to-head dimer and cooperatively recognize the antigen in the dimer interface. This "antigen clasping" produced an expansive interface where trimethylated Lys bound to an unusually extensive aromatic cage in one Fab and the histone N terminus to a pocket in the other, thereby rationalizing the high specificity. A long-neck antibody format with a long linker between the antigen-binding module and the Fc region facilitated antigen clasping and achieved both high specificity and high potency. Antigen clasping substantially expands the paradigm of antibody-antigen recognition and suggests a strategy for developing extremely specific antibodies. |
| Databáze: | OpenAIRE |
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