4YHP

Crystal structure of 309M3-B Fab in complex with H3K9me3 peptide

Summary for 4YHP

• Entry DOI: 10.2210/pdb4yhp/pdb
• Related: 4YHP 4YHZ
• Descriptor: H3K9me3 peptide, Fab Heavy Chain, Fab Light Chain, ... (4 entities in total)
• Functional Keywords: antibody, fab, head-to-head dimerization, h3k9me3, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 10
• Total formula weight: 195171.11

Authors

Hattori, T.,Dementieva, I.S.,Montano, S.P.,Koide, S. (deposition date: 2015-02-27, release date: 2016-02-10, Last modification date: 2023-09-27)

Primary citation

Hattori, T.,Lai, D.,Dementieva, I.S.,Montano, S.P.,Kurosawa, K.,Zheng, Y.,Akin, L.R.,Swist-Rosowska, K.M.,Grzybowski, A.T.,Koide, A.,Krajewski, K.,Strahl, B.D.,Kelleher, N.L.,Ruthenburg, A.J.,Koide, S.
Antigen clasping by two antigen-binding sites of an exceptionally specific antibody for histone methylation.
Proc.Natl.Acad.Sci.USA, 113:2092-2097, 2016

PubMed Abstract: 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.

PubMed: 26862167
DOI: 10.1073/pnas.1522691113

Experimental method

X-RAY DIFFRACTION (2.53 Å)