Fig. 3: Crystallographic studies reveal the binding mode of the GM4 macrocyclic peptide at the Mpro active site. | Nature Chemistry

Fig. 3: Crystallographic studies reveal the binding mode of the GM4 macrocyclic peptide at the Mpro active site.

From: In vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-amino acids targeting the SARS-CoV-2 main protease

Fig. 3

a, GM4 binds in the substrate binding cleft of both protomers A and B in the Mpro dimer. b, Structure of GM4; the H3GM4 carbonyl O is indicated with an arrow. c, Polder omit map of GM4 contoured at a level of ±1.5 standard deviation (σ). d, View of GM4 at the active site. The H41 and C145 catalytic dyad is in orange. γ14GM4 (magenta) occupies the S1′ pocket; the side chains of H3GM4, F2GM4 and Acy1GM4 occupy the S1, S2 and S4 pockets, respectively. e,f, Close-ups of the S1 pocket, showing the H3GM4 backbone carbonyl in the oxyanion hole (C145, G143 backbone amides). The backbone NH of H3GM4 is positioned to interact with the H164 backbone CO. The H3GM4 imidazole is positioned to hydrogen bond with the H163 side chain and to interact with the E166 side chain, which interacts with S1 of protomer B, as observed in apo-Mpro structures. Y9GM4 is 3.1 Å and 3.3 Å from the E166 and S1B side chains, respectively. g, Nirmatrelvir with the residues occupying the S1−S4 subsites labelled P1−P4 (the reactive nitrile is indicated with an arrow). h, Superimposition of views from crystal structures of Mpro with GM4 and nirmatrelvir (Protein Data Bank 7VH8 (ref. 60)). GM4 non-covalently interacts at the active site, while the nitrile of nirmatrelvir reacts with C145. Note the similar locations of the nirmatrelvir nitrile-derived N and the H3GM4 carbonyl O.

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