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Crystal structure of 309M3-B in complex with trimethylated Lys
Structural highlights
Publication Abstract from PubMedAntibodies 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. Antigen clasping by two antigen-binding sites of an exceptionally specific antibody for histone methylation.,Hattori T, Lai D, Dementieva IS, Montano SP, Kurosawa K, Zheng Y, Akin LR, Swist-Rosowska KM, Grzybowski AT, Koide A, Krajewski K, Strahl BD, Kelleher NL, Ruthenburg AJ, Koide S Proc Natl Acad Sci U S A. 2016 Feb 9. pii: 201522691. PMID:26862167[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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