Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain

By K. Anand, G. Palm, J. Mesters, S. Siddell, J. Ziebuhr, Rolf Hilgenfeld. EMBO Journal, 2002

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The key enzyme in coronavirus polyprotein processing is the viral main proteinase, Mpro, a protein with extremely low sequence similarity to other viral and cellular proteinases. Here, the crystal structure of the 33.1 kDa transmissible gastroenteritis (corona)virus Mpro is reported. The structure was refined to 1.96 Å resolution and revealed three dimers in the asymmetric unit. The mutual arrangement of the protomers in each of the dimers suggests that Mpro self‐processing occurs in trans. The active site, comprised of Cys144 and His41, is part of a chymotrypsin‐like fold that is connected by a 16 residue loop to an extra domain featuring a novel α‐helical fold. Molecular modelling and mutagenesis data implicate the loop in substrate binding and elucidate S1 and S2 subsites suitable to accommodate the side chains of the P1 glutamine and P2 leucine residues of Mpro substrates. Interactions involving the N‐terminus and the α‐helical domain stabilize the loop in the orientation required for trans‐cleavage activity. The study illustrates that RNA viruses have evolved unprecedented variations of the classical chymotrypsin fold.

Subfields: Animal Science and Zoology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/1b13d41793af028f89225c0b951c9810418ea27b

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Citations in the corpus

Nidovirales: Evolving the largest RNA virus genome (2006, background): “The crystal structures of oronavirus and arterivirus 3CLpros revealed that both groups f enzymes have a three-domain structure, with domains I and I forming a (chymotrypsin-like) two-ß-barrel fold consisting f 12 or 13 ß-strands (Anand et al., 2002, 2003; Barrette-Ng t al., 2002; Yang et al., 2003).”
Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease (2020, background): “The protease inhibitors are grouped based on their targets and mechanism of action and include proteasome inhibitors (1) (2) (3) (4) (5) (6) (7) (8) ; HIV protease inhibitors (9) (10) (11) (12) (13) (14) ; γ-secretase inhibitors (15) (16) (17) (18) (19) (20) (21) (22) ; HCV NS3-4A protease inhibitor”
The Molecular Biology of Coronaviruses (2006, background): “Crystal structures have been solved for Mpro for HCoV-229E (Anand et al., 2002), TGEV (Anand et al., 2003), and SARS-CoV (Yang et al., 2003).”
Mechanisms and enzymes involved in SARS coronavirus genome expression. (2003, background): “Furthermore, 3CLpro is the only coronavirus protein for which structure information is available (Anand et al., 2002, 2003).”
Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach (2020, unknown): “1 3C-like proteinase and main proteinase Involved in viral polyprotein processing during replication [46].”
From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design (2014, background): “Published in 2002 [29] , the structure revealed that the M pro is a dimer (cf.”
Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19 (2020, background): “Mpro is a homodimer with three structural domains, domain I, II and III (Anand et al., 2002).”