7NF5

Crystal structure of MG-132 covalently bound to the main protease (3CLpro/Mpro) of SARS-CoV-2 in spacegroup C2.

Summary for 7NF5

• Entry DOI: 10.2210/pdb7nf5/pdb
• Related PRD ID: PRD_001210
• Descriptor: 3C-like proteinase, N-[(benzyloxy)carbonyl]-L-leucyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-L-leucinamide, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: sars-cov-2, mpro, 3clpro, exscalate4cov, drug discovery, elettra, viral protein, mg-132
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34825.64

Authors

Costanzi, E.,Demitri, N.,Giabbai, B.,Storici, P. (deposition date: 2021-02-05, release date: 2021-04-07, Last modification date: 2024-01-31)

Primary citation

Costanzi, E.,Kuzikov, M.,Esposito, F.,Albani, S.,Demitri, N.,Giabbai, B.,Camasta, M.,Tramontano, E.,Rossetti, G.,Zaliani, A.,Storici, P.
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.

PubMed: 34769210
DOI: 10.3390/ijms222111779

Experimental method

X-RAY DIFFRACTION (1.94 Å)