8DSU

Crystal Structure of SARS CoV-2 Mpro with Pfizer Intravenous Inhibitor PF-00835231

Summary for 8DSU

• Entry DOI: 10.2210/pdb8dsu/pdb
• Descriptor: 3C-like proteinase nsp5, GLYCEROL, N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide, ... (5 entities in total)
• Functional Keywords: coronavirus, covid-19, covid, protease, drug resistance, complex, hydrolase, durg discovery, main protease, mpro, substrate complex, pfizer iv compound, pf-00835231, viral protein, viral protein-hydrolase-inhibitor complex, viral protein/hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68940.65

Authors

Shaqra, A.M.,Schiffer, C.A. (deposition date: 2022-07-22, release date: 2023-03-29, Last modification date: 2024-10-23)

Primary citation

Zvornicanin, S.N.,Shaqra, A.M.,Huang, Q.J.,Ornelas, E.,Moghe, M.,Knapp, M.,Moquin, S.,Dovala, D.,Schiffer, C.A.,Kurt Yilmaz, N.
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses.
Viruses, 15:-, 2023

PubMed Abstract: With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose a potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (M) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from the beluga whale. A comparison with the apo structure of SW1 M, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 M. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors.

PubMed: 36992489
DOI: 10.3390/v15030781

Experimental method

X-RAY DIFFRACTION (1.86 Å)