4U6H

Vaccinia L1/M12B9-Fab complex

Summary for 4U6H

• Entry DOI: 10.2210/pdb4u6h/pdb
• Descriptor: Heavy chain of murine anti-vaccinia L1 IgG2a antibody M12B9, Light chain of murine anti-vaccinia L1 IgG2a antibody M12B9, Protein L1 (3 entities in total)
• Functional Keywords: igg2a, fab, heavy chain light chain, immune system
• Biological source: Vaccinia virus (VACV); More
• Total number of polymer chains: 6
• Total formula weight: 134798.36

Authors

Matho, M.H.,Schlossman, A.,Zajonc, D.M. (deposition date: 2014-07-29, release date: 2014-08-06, Last modification date: 2023-09-27)

Primary citation

Kaever, T.,Meng, X.,Matho, M.H.,Schlossman, A.,Li, S.,Sela-Culang, I.,Ofran, Y.,Buller, M.,Crump, R.W.,Parker, S.,Frazier, A.,Crotty, S.,Zajonc, D.M.,Peters, B.,Xiang, Y.
Potent neutralization of vaccinia virus by divergent murine antibodies targeting a common site of vulnerability in l1 protein.
J.Virol., 88:11339-11355, 2014

PubMed Abstract: Vaccinia virus (VACV) L1 is an important target for viral neutralization and has been included in multicomponent DNA or protein vaccines against orthopoxviruses. To further understand the protective mechanism of the anti-L1 antibodies, we generated five murine anti-L1 monoclonal antibodies (MAbs), which clustered into 3 distinct epitope groups. While two groups of anti-L1 failed to neutralize, one group of 3 MAbs potently neutralized VACV in an isotype- and complement-independent manner. This is in contrast to neutralizing antibodies against major VACV envelope proteins, such as H3, D8, or A27, which failed to completely neutralize VACV unless the antibodies are of complement-fixing isotypes and complement is present. Compared to nonneutralizing anti-L1 MAbs, the neutralization antibodies bound to the recombinant L1 protein with a significantly higher affinity and also could bind to virions. By using a variety of techniques, including the isolation of neutralization escape mutants, hydrogen/deuterium exchange mass spectrometry, and X-ray crystallography, the epitope of the neutralizing antibodies was mapped to a conformational epitope with Asp35 as the key residue. This epitope is similar to the epitope of 7D11, a previously described potent VACV neutralizing antibody. The epitope was recognized mainly by CDR1 and CDR2 of the heavy chain, which are highly conserved among antibodies recognizing the epitope. These antibodies, however, had divergent light-chain and heavy-chain CDR3 sequences. Our study demonstrates that the conformational L1 epitope with Asp35 is a common site of vulnerability for potent neutralization by a divergent group of antibodies.

PubMed: 25031354
DOI: 10.1128/JVI.01491-14

Experimental method

X-RAY DIFFRACTION (3.1 Å)