6v4r
Crystal structure of a chimeric MR78-like antibody chimera-1 Fab
Structural highlights
Publication Abstract from PubMedMarburg 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 naive 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-naive 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-naive 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. Discovery of Marburg virus neutralizing antibodies from virus-naive human antibody repertoires using large-scale structural predictions.,Bozhanova NG, Sangha AK, Sevy AM, Gilchuk P, Huang K, Nargi RS, Reidy JX, Trivette A, Carnahan RH, Bukreyev A, Crowe JE Jr, Meiler J Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31142-31148. doi: , 10.1073/pnas.1922654117. Epub 2020 Nov 23. PMID:33229516[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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