1918 influenza A virus (IAV) caused the worst flu pandemic in human history (a. k. a. the Spanish flu). Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAVs. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. However, the molecular recognition mechanisms underlying the hijacking host proteins by the pandemic 1918 NS1 remain unknown. One important pathway by which NS1 increases IAV virulence is to activate phosphoinositide 3 kinase (PI3K) through binding to its p85b subunit. Here, using NMR spectroscopy, small-angle X-ray scattering, and X-ray crystallography, we investigate the molecular basis by which the 1918 NS1 effector domain (NS1ED) binds human p85b subunit. Structure determination of 1918 NS1ED in the free and p85b-bound forms, and NMR relaxation dispersion experiments revealed that the free 1918 NS1ED undergoes a dynamic conformational switch in the sub-millisecond timescale between p85b-binding-incompetent and -competent states. Combined with kinetic analysis, we present that binding of 1918 NS1ED and p85b is well-represented by conformational selection binding mechanism, in which the dynamic motion of free 1918 NS1ED controls the overall binding process. Moreover, comparison of NS1ED structures of diverse IAV strains indicated that the structural adaption occurring through the dynamic conformational exchange might be a prevalent mechanism among NS1 proteins.

Structural and dynamic mechanisms of hijacking human phosphoinositide 3-kinase by nonstructural protein 1 of the 1918 Spanish flu virus

2019 Fall National Meeting

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