Lee Peter S, Arnell Ashley J, Wilson Ian A
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Acta Crystallogr F Struct Biol Commun. 2015 Feb;71(Pt 2):145-8. doi: 10.1107/S2053230X14027599. Epub 2015 Jan 28.
Influenza viruses remain a persistent challenge to human health owing to their inherent ability to evade the immune response by antigenic drift. However, the discovery of broadly neutralizing antibodies (bnAbs) against divergent viruses has sparked renewed interest in a universal influenza vaccine and novel therapeutic opportunities. Here, a crystal structure at 1.70 Å resolution is presented of the Fab of the human antibody CH65, which has broad neutralizing activity against a range of seasonal H1 isolates. Previous studies proposed that affinity maturation of this antibody lineage pre-organizes the complementarity-determining region (CDR) loops into an energetically favorable HA-bound conformation. Indeed, from the structural comparisons of free and HA-bound CH65 presented here, the CDR loops, and in particular the heavy-chain CDR3, adopt the same conformations in the free and bound forms. Thus, these findings support the notion that affinity maturation of the CH65 lineage favorably preconfigures the CDR loops for high-affinity binding to influenza hemagglutinin.
由于流感病毒具有通过抗原漂移逃避免疫反应的内在能力，它们仍然是对人类健康的持续挑战。然而，针对不同病毒的广泛中和抗体（bnAbs）的发现，引发了人们对通用流感疫苗和新型治疗机会的新兴趣。在此展示了人类抗体CH65的Fab片段的晶体结构，分辨率为1.70 Å，该抗体对一系列季节性H1分离株具有广泛的中和活性。先前的研究提出，该抗体谱系的亲和力成熟将互补决定区（CDR）环预组织成能量有利的HA结合构象。实际上，从这里展示的游离和HA结合的CH65的结构比较来看，CDR环，特别是重链CDR3，在游离和结合形式中采用相同的构象。因此，这些发现支持了这样一种观点，即CH65谱系的亲和力成熟有利于将CDR环预配置为与流感血凝素高亲和力结合。
