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Activity inhibition and crystal polymorphism induced by active-site metal swapping

Abstract : The Arenaviridae family is one of the two RNA viral families encoding a 3'-5' exonuclease in their genome. An exonuclease domain is carried by the Arenaviridae Nucleoprotein and targets dsRNA specifically. This domain is directly involved in suppression of innate immunity in the host cell. Like most phosphate-processing enzymes, it requires a divalent metal ion such as Mg 2+ (or Mn 2+) as a cofactor to catalyse nucleotide cleavage and transfer reactions. On the other hand, Calcium (Ca 2+) inhibits this enzymatic activity, in spite of the fact that Mg 2+ and Ca 2+ are presenting comparable binding affinities and biological availability. Here, we study the molecular and structural effect of the calcium replacing the magnesium and its inhibition mechanism for phosphodiester cleavage, an essential reaction in the viral process of innate immunity suppression. We present for the first time the biochemical data and two high resolution structures of Mopeia virus exonuclease domain complexed with each ion respectively. We outline the consequences of the ion swap on the protein's stability, the catalytic site, and the functional role of a specific metal ion to enable the catalytic cleavage of a dsRNA substrate.
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Submitted on : Wednesday, December 16, 2020 - 4:47:14 PM
Last modification on : Tuesday, March 23, 2021 - 3:22:05 PM
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Elsie Yekwa, Joelle Khourieh, Bruno Canard, Nicolas Papageorgiou, Francois Ferron. Activity inhibition and crystal polymorphism induced by active-site metal swapping. Acta crystallographica. Section D, Structural biology, International Union of Crystallography, 2017, 73 (8), pp.641-649. ⟨10.1107/S205979831700866X⟩. ⟨hal-03078421⟩

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