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Figure 4
Comparative structural analysis of inhibitor-bound and ligand-free 3C protease. (A) Chemical structures of AG7404 (top) and rupintrivir (bottom), highlighting distinct P2 and P3 substituents (blue) and the covalent warhead (red asterisk). (B) Superposition of active-site regions from AG7404-bound hRV-B14 3C protease (cyan) and rupintrivir-bound hRV-A2 3C protease (yellow; PDB ID 1cqq). Key features (βcII, βdII, Ser127/Ser128, His40) and inhibitor positions are indicated. (C) Close-up view of the βcII–βdII region in AG7404-bound hRV-B14 3C protease (cyan, left) and rupintrivir-bound hRV-A2 3C protease (yellow, right). Representative distances are annotated. (D) Overlay of AG7404-bound (cyan), apo-form NMR (orange; PDB ID 2in2), ligand-free scFc(YDF)-bound (green; PDB ID 6kyz) and ligand-free scFc(GGVV)-bound (pink; PDB ID 6kz0) hRV-B14 3C protease structures, illustrating the diversity and disorder of the βcII–βdII region. In the right-hand box, an NMR ensemble shows the conformational variability of the βcII–βdII loop (orange).

IUCrJ
Volume 13| Part 1| January 2026| Pages 19-30
ISSN: 2052-2525
https://doi.org/10.1107/S2052252525008929