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. 2024 Jun 28;300(8):107514. doi: 10.1016/j.jbc.2024.107514

Figure 3.

Figure 3

Largely driven by the nature of the 4’ pocket and the specifics of how the 2’-OH is recognized by the polymerase. GS-646939 is shown in magenta. HRV (A) and SARS-CoV-2 (B) have a similar overall active site structure, differing primarily at Gly-326/Ser-759 and Tyr-238/Cys-622. While somewhat different from HRV and SARS-CoV-2, RSV (C) and PIV5 also have a similar overall structure, differing primarily at Phe-704/Tyr-667 and Asn-705/Cys-668. In each case, the 4ʹ-cyano of GS-646939 is at least tolerated. The interaction between the 4ʹ-cyano and Asn-296 in HRV appears to be particularly ideal and is likely responsible for the inhibitor’s increased affinity compared to ATP. HRV, human rhinovirus; PIV-5, parainfluenza virus 5; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.