6V4R

Crystal structure of a chimeric MR78-like antibody chimera-1 Fab

6V4R の概要

• エントリーDOI: 10.2210/pdb6v4r/pdb
• 分子名称: Chimera-1 Fab heavy chain, Chimera-1 Fab light chain (2 entities in total)
• 機能のキーワード: marburg virus, antibody, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47494.77

構造登録者

Bozhanova, N.G.,Crowe, J.E.,Meiler, J. (登録日: 2019-11-28, 公開日: 2020-11-25, 最終更新日: 2024-10-23)

主引用文献

Bozhanova, N.G.,Sangha, A.K.,Sevy, A.M.,Gilchuk, P.,Huang, K.,Nargi, R.S.,Reidy, J.X.,Trivette, A.,Carnahan, R.H.,Bukreyev, A.,Crowe Jr., J.E.,Meiler, J.
Discovery of Marburg virus neutralizing antibodies from virus-naive human antibody repertoires using large-scale structural predictions.
Proc.Natl.Acad.Sci.USA, 117:31142-31148, 2020

PubMed Abstract: Marburg virus (MARV) disease is lethal, with fatality rates up to 90%. Neutralizing antibodies (Abs) are promising drug candidates to prevent or treat the disease. Current efforts are focused in part on vaccine development to induce such MARV-neutralizing Abs. We analyzed the antibody repertoire from healthy unexposed and previously MARV-infected individuals to assess if naïve repertoires contain suitable precursor antibodies that could become neutralizing with a limited set of somatic mutations. We computationally searched the human Ab variable gene repertoire for predicted structural homologs of the neutralizing Ab MR78 that is specific to the receptor binding site (RBS) of MARV glycoprotein (GP). Eight Ab heavy-chain complementarity determining region 3 (HCDR3) loops from MARV-naïve individuals and one from a previously MARV-infected individual were selected for testing as HCDR3 loop chimeras on the MR78 Ab framework. Three of these chimerized antibodies bound to MARV GP. We then tested a full-length native Ab heavy chain encoding the same 17-residue-long HCDR3 loop that bound to the MARV GP the best among the chimeric Abs tested. Despite only 57% amino acid sequence identity, the Ab from a MARV-naïve donor recognized MARV GP and possessed neutralizing activity against the virus. Crystallization of both chimeric and full-length native heavy chain-containing Abs provided structural insights into the mechanism of binding for these types of Abs. Our work suggests that the MARV GP RBS is a promising candidate for epitope-focused vaccine design to induce neutralizing Abs against MARV.

PubMed: 33229516
DOI: 10.1073/pnas.1922654117

実験手法

X-RAY DIFFRACTION (3.48 Å)