Fig. 4: Two independent mechanisms of inhibition prevent WRN binding ssDNA. | Communications Biology

Fig. 4: Two independent mechanisms of inhibition prevent WRN binding ssDNA.

From: Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery

Fig. 4: Two independent mechanisms of inhibition prevent WRN binding ssDNA.

ssDNA was immobilised on a chip and binding of: WRN + ATPγS; or WRN + ATPγS in the presence of GSK_WRN3, HRO761 or VVD Example 81 was measured using SPR. a Summary plot of the kinetic response of each condition shows that all inhibitors block WRN binding to ssDNA. b Using a bodipy-ATPγS competition assay, in the absence of DNA, inhibitor concentration response curves show differentiated mechanisms of inhibition for VVD-133214 (yellow) compared to HRO761 (blue) and GSK_WRN3 (orange). Data shown as individual data points from n = 3 technical replications. c Overlay of WRN in complex with molecule 81 + no nucleotide (yellow), with WRN + VVD-133214 + ADP (PDB 7GQU, grey), shows a consistent protein fold at the inhibitor binding site independent of nucleotide presence. d Overlay of WRN in complex with molecule 81 + no nucleotide (yellow) with the apo structure (pink) shows a conserved fold in the nucleotide binding site and a conserved H-bond network.

Back to article page