7RCH

Crystal structure of NS1-ED of Vietnam influenza A virus in complex with the p85-beta-iSH2 domain of human PI3K

Summary for 7RCH

• Entry DOI: 10.2210/pdb7rch/pdb
• Descriptor: Non-structural protein 1, Phosphatidylinositol 3-kinase regulatory subunit beta (2 entities in total)
• Functional Keywords: vietnam influenza a virus, ns1, pi3k, viral protein
• Biological source: Influenza A virus (A/Viet Nam/1203/2004(H5N1)); More
• Total number of polymer chains: 4
• Total formula weight: 68025.32

Authors

Kim, I.,Zhao, B.,Li, P.,Cho, J.H. (deposition date: 2021-07-07, release date: 2022-07-13, Last modification date: 2023-10-18)

Primary citation

Kim, I.,Dubrow, A.,Zuniga, B.,Zhao, B.,Sherer, N.,Bastiray, A.,Li, P.,Cho, J.H.
Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.
Nat Commun, 13:5775-5775, 2022

PubMed Abstract: Elucidating how individual mutations affect the protein energy landscape is crucial for understanding how proteins evolve. However, predicting mutational effects remains challenging because of epistasis-the nonadditive interactions between mutations. Here, we investigate the biophysical mechanism of strain-specific epistasis in the nonstructural protein 1 (NS1) of influenza A viruses (IAVs). We integrate structural, kinetic, thermodynamic, and conformational dynamics analyses of four NS1s of influenza strains that emerged between 1918 and 2004. Although functionally near-neutral, strain-specific NS1 mutations exhibit long-range epistatic interactions with residues at the p85β-binding interface. We reveal that strain-specific mutations reshaped the NS1 energy landscape during evolution. Using NMR spin dynamics, we find that the strain-specific mutations altered the conformational dynamics of the hidden network of tightly packed residues, underlying the evolution of long-range epistasis. This work shows how near-neutral mutations silently alter the biophysical energy landscapes, resulting in diverse background effects during molecular evolution.

PubMed: 36182933
DOI: 10.1038/s41467-022-33554-9

Experimental method

X-RAY DIFFRACTION (3.1 Å)