题目：Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody

报告人：Huafeng Xu

D. E. Shaw Research LLC.

时间：2012年11月28日上午10：00

地点：成都生物所综合楼二楼会议室

Abstract:

Several broadly neutralizing antibodies against influenza have recently been identified. These antibodies target conserved epitopes on influenza hemagglutinin and thus cannot be easily circumvented by mutant viral strains. Their discovery raises the possibility of “universal flu vaccines”, which may act across seasonal strains by eliciting such broadly neutralizing antibodies. We investigate the affinity maturation of one B-cell lineage from a human subject expressing broadly neutralizing antibodies against H1 influenza strains, by analyzing the difference in immunogen-binding among four antibodies in the lineage—two mature antibodies, the unmutated common ancestor, and a common intermediate. X-ray crystallography, together with long time-scale molecular dynamics (MD) simulations, show that all antibodies bind in similar conformations to the conserved receptor-binding pocket in the head domain of influenza hemagglutinin. Further MD simulations suggest that the CDR H3 loops in the mature antibodies become more fixed in the conformation ready for antigen-binding, compared to the much more flexible CDR H3 loops in the unmutated common ancestor and the common intermediate. Kinetic measurements suggest that this pre-configuration accounts for most of the affinity gain. Our results inform the strategies for developing more broadly effective influenza vaccines.

成都生物所天然产物中心

2012-11-26