The Enzymatic Mechanism of OAS: How Metal Ions and Quantum Effects Help Activate Innate Immunity

2′-5′-Oligoadenylate synthetases (OAS)
are crucial
innate immune sensors that activate antiviral responses upon detecting
viral double-stranded RNA. Understanding the molecular mechanism of
OAS is vital for advancing immunomodulatory therapies. This study
provides a detailed enzymatic mechanism of the OAS, integrating structural,
kinetic, and quantum chemical analyses. Crystallographic data of the
OAS1 postreactive complexes shed light on the geometry of OAS1 following
product formation and dissociation, the sequential order of product
release, and the pivotal role of divalent metal ions in catalysis.
Our data reveal the unanticipated involvement of a third metal ion,
which may play a transient supporting role in the catalytic cycle.
Moreover, they highlight the central role of quantum mechanisms in
the OAS function. Strikingly, substituting catalytic Mg2+ with Mn2+ ions increases the substrate binding rate 9-fold
and activates OAS for catalysis. The results of this study are pertinent
to the OAS/cGAS family of innate immune sensors and offer insights
that can be applied to a broader class of nucleotidyltransferases,
which play key roles in various biological processes.