Fig. 2: Detailed mapping of the HPI binding pocket between HSV-1 UL5 and UL52.
From: Structural and mechanistic insights into herpesvirus helicase–primase and its therapeutic inhibitors
a, Superimposition of the AMNV and PTV binding sites, using Cα atoms from both structures as reference points. AMNV and PTV are shown as stick models. b,c, Close-up views of the PTV (b) and AMNV (c) binding sites, with interaction residues (UL52 F306, A899, N902, UL5 N98, N343, K356, E359 and Y882) shown as sticks. Resistance mutant residues that form van der Waals interactions (G352 and M355) are also shown as sticks. Polar interactions are represented by yellow dashed lines, with numbers indicating approximate distances in Å. d,e, Proposed models explaining the PTV resistance associated with the HSV-1 UL52 A899T (and the HSV-2 UL52 A906V) substitution and the susceptibility of the VZV HP complex to AMNV (a valine is located at the equivalent position of UL52 A899 in VZV). The models show the most favourable rotamers for A899T (d) and A899V (e), with distances in Å between the side chains of the modelled threonine and valine residues to the PTV sulfonamide and AMNV sulfone head, respectively. f, Inhibition of viral DNA replication by PTV (solid) and AMNV (dotted) in ARPE-19 cells infected with HSV-2 WT (black) or a UL52 A906V variant (red). Representative dose–response curves from n = 3 independent biological replicates. Data are mean ± standard deviation from six replicates per condition.
