A cryptic pocket in Ebola VP35 allosterically controls RNA binding

Matthew A. Cruz, Thomas E. Frederick, Upasana L. Mallimadugula, Sukrit Singh, Neha Vithani, Maxwell I. Zimmerman, Justin R. Porter, Katelyn E. Moeder, Gaya K. Amarasinghe and Gregory R. Bowman ()
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Matthew A. Cruz: Washington University School of Medicine
Thomas E. Frederick: Washington University School of Medicine
Upasana L. Mallimadugula: Washington University School of Medicine
Sukrit Singh: Washington University School of Medicine
Neha Vithani: Washington University School of Medicine
Maxwell I. Zimmerman: Washington University School of Medicine
Justin R. Porter: Washington University School of Medicine
Katelyn E. Moeder: Washington University School of Medicine
Gaya K. Amarasinghe: Washington University School of Medicine
Gregory R. Bowman: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola’s replication cycle but lacks pockets that present obvious utility for drug design. Using adaptive sampling simulations and machine learning algorithms, we predict VP35 harbors a cryptic pocket that is allosterically coupled to a key dsRNA-binding interface. Thiol labeling experiments corroborate the predicted pocket and mutating the predicted allosteric network supports our model of allostery. Finally, covalent modifications that mimic drug binding allosterically disrupt dsRNA binding that is essential for immune evasion. Based on these results, we expect this pipeline will be applicable to other proteins.

Date: 2022
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DOI: 10.1038/s41467-022-29927-9

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