贪婪
血凝素(流感)
低聚物
三聚体
结合位点
糖蛋白
血浆蛋白结合
病毒蛋白
生物
中和抗体
细胞生物学
蛋白质结构
化学
抗体
计算生物学
生物物理学
病毒学
生物化学
病毒
遗传学
有机化学
二聚体
作者
Eva-Maria Strauch,Steffen M. Bernard,Lawrence A. David,Alan Bohn,Peter S. Lee,Caitlin Anderson,Travis Nieusma,Carly A. Holstein,Natalie K. Garcia,Kathryn A. Hooper,Rashmi Ravichandran,Jorgen Nelson,William Sheffler,Jesse D Bloom,Kelly K. Lee,Andrew B. Ward,Paul Yager,Deborah H. Fuller,Ian A. Wilson,David Baker
摘要
Many viral surface glycoproteins and cell surface receptors are homo-oligomers, and thus can potentially be targeted by geometrically matched homo-oligomers that engage all subunits simultaneously to attain high avidity and/or lock subunits together. The adaptive immune system cannot generally employ this strategy since the individual antibody binding sites are not arranged with appropriate geometry to simultaneously engage multiple sites in a single target homo-oligomer. We describe a general strategy for the computational design of homo-oligomeric protein assemblies with binding functionality precisely matched to homo-oligomeric target sites. In the first step, a small protein is designed that binds a single site on the target. In the second step, the designed protein is assembled into a homo-oligomer such that the designed binding sites are aligned with the target sites. We use this approach to design high-avidity trimeric proteins that bind influenza A hemagglutinin (HA) at its conserved receptor binding site. The designed trimers can both capture and detect HA in a paper-based diagnostic format, neutralizes influenza in cell culture, and completely protects mice when given as a single dose 24 h before or after challenge with influenza.
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