Targeting structural dynamics of the RNA-dependent RNA polymerase for anti-viral strategies

Ligand Binding Enhances Millisecond Conformational Exchange in Xylanase B2 from Streptomyces lividans

“…It was previously demonstrated that protein flexibility and coordinated residue motions play an important role in catalysis for a variety of enzyme systems, such as dihydrofolate reductase, 51 RNA-dependent RNA polymerase, 52 and ribonuclease. 53 A number of studies have also investigated the fast time-scale dynamics in GH11 xylanases.…”

Picornaviral polymerase structure, function, and fidelity modulation

“…This study used 1 H and 13 C NMR with [ methyl - 13 C] methionine to provide sparse labels located throughout the polymerase, an approach that can be used to directly measure protein dynamics in solution. 3D pol is too large for full-blown NMR structure determination, but sparse labeling schemes have proven to be very effective, especially when applied to 3D pol -RNA and 3D pol -RNA-NTP complexes (Boehr et al, 2014; Yang et al, 2010). The NMR signal from Met355, located in motif D and only four residues away from Lys359, is sensitive to both NTP binding and the open versus closed state of the active site, providing observable differences between correct and incorrect nucleotides in the active site.…”

The not-so-infinite malleability of RNA viruses: Viral and cellular determinants of RNA virus mutation rates

“…The intrinsic fidelity of viral RdRps is governed by multiple biochemical and biophysical checkpoints, such as conformational changes, mediated by amino acids proximal to and distal from the RdRp active site (reviewed in [8]). Studies with poliovirus 3D pol provided the first descriptions of high-and low-fidelity RdRp variants [9,10].…”