An extended conformation of SARS-CoV-2 main protease reveals allosteric targets

Abstract

Significance The coronavirus main protease (M pro ) is required for viral replication. Here, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M pro by trapping it with nanobodies and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. Another monomeric state is termed compact conformation and is similar to one protomer of the dimeric form. We designed a Nanoluc Binary Techonology (NanoBiT)-based high-throughput allosteric inhibitor assay based on structural conformational change. Our results provide insight into the maturation, dimerization, and catalysis of the coronavirus M pro and pave a way to develop an anticoronaviral drug through targeting the maturation process to inhibit the autocleavage of M pro .

Molecular interactions and inhibition of the SARS‐CoV‐2 main protease by a thiadiazolidinone derivative

“…However, in our work, we also report on a residue community analysis of the enzyme, which notably suggested that CCG‐50014 disrupted inter‐community correlations stemming for the catalytic residues C145 and H41. These observations highlight the role of allostery in this enzyme, which could prove useful in designing potential therapeutics targeting the enzyme via an allosteric mechanism 75–77 …”

“…These observations highlight the role of allostery in this enzyme, which could prove useful in designing potential therapeutics targeting the enzyme via an allosteric mechanism. 75 , 76 , 77 …”

Biochemical and structural insights into SARS-CoV-2 polyprotein processing by Mpro

“…In this sense, El-Baba and colleagues ( 61 ) identified that fragment JGY—discovered through crystallographic fragment screening and binding in the dimer interface ( 30 )—destabilized the Mpro dimer and showed ∼35% inhibition of the rate of processing at 100 μM. Along the same lines, Sun and colleagues ( 62 ) discovered a nanobody, NB2B4, which binds the C-terminal domain of monomeric Mpro (PDB 7VFB) and inhibits activity with an IC 50 ∼150 nM. Thus, destabilization of the Mpro catalytic dimer may contribute to the mechanism of inhibition.…”

Understanding the role of water on temperature-dependent structural modifications of SARS CoV-2 main protease binding sites

“…The model retrieved from PDB is the monomer form of protease. However, the global stoichiometry of the protease is homodimer [6] , [37] . Therefore, for the dimer simulations, protein-protein docking was carried out using HDOCK server [38] .…”