Fig. 4: Resistance mechanism of wildtype NiV polymerase against broad-spectrum allosteric inhibitor GHP-88309. | Nature Communications

Fig. 4: Resistance mechanism of wildtype NiV polymerase against broad-spectrum allosteric inhibitor GHP-88309.

From: Cryo-EM structure of Nipah virus L-P polymerase complex

Fig. 4

a Superimposition of structures of NiV wildtype and LH1165Y mutant polymerase. b Close-up of the mutant site. In the WT polymerase, the H1165 could form a hydrogen bond with the side chain of E922 and make the side chain flip to get away from the interface of RdRp and Capping domains which will lose the interaction with the GHP-88309. While, for the LH1165Y mutant polymerase, the side chain of Y1165 could not form a hydrogen bond with the E922 remaining toward the binding sites of GHP-88309. The structure of wildtype NiV L protein was colored by domains as Fig. 2. The structure of the H1165Y mutant was shown in white. c Sequence alignment of the L protein of paramyxovirus. The sequence alignment was performed using T-coffee73 (https://tcoffee.crg.eu/) and the figure was prepared by ESPript 3.074 (https://espript.ibcp.fr). d Structural comparison of different polymerases in the mutant site. In the structure of HPIV3, the conformation of E863 is like that of NiV LH1165Y mutant polymerase. HeV Hendra virus, LayV Langya virus, MojV Mojiang virus, MeV measles virus, HPIV3 Human parainfluenza virus 3.

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