9OPM

Crystal Structure of SARS-CoV-2 Mpro S147A in complex with Pfizer Intravenous Inhibitor PF-00835231

9OPM の概要

• エントリーDOI: 10.2210/pdb9opm/pdb
• 分子名称: 3C-like proteinase nsp5, 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 (3 entities in total)
• 機能のキーワード: sars2, sars-cov-2, mpro, s147a, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68568.19

構造登録者

Zvornicanin, S.N.,Shaqra, A.M.,Schiffer, C.A. (登録日: 2025-05-19, 公開日: 2025-12-10, 最終更新日: 2026-01-28)

主引用文献

Zvornicanin, S.N.,Shaqra, A.M.,Flynn, J.,Intravaia, L.E.,Martinez, H.C.,Jia, W.,Gupta, D.K.,Moquin, S.,Dovala, D.,Bolon, D.N.,Kelch, B.A.,Schiffer, C.A.,Yilmaz, N.K.
Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease.
Sci Adv, 12:eaeb0769-eaeb0769, 2026

PubMed Abstract: The coronaviral main protease (M) has been the subject of various biochemical and structural studies and a drug target against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. SARS-CoV-2 M is active as a dimer, but despite apparent cooperativity in catalytic activity, how the two distal active sites communicate and modulate binding and/or catalysis is unclear. Here, we have investigated the interplay between cooperativity, dimerization, and substrate cleavage in SARS-CoV-2 M through a combination of enzymatic assays, crystal structures, and protein characterization. To disentangle the contribution of each active site to the observed enzymatic activity, we developed a cleavage assay involving heterodimers of active and inactive (catalytic residue mutated or inhibitor-bound) monomers. Notably, we found that heterodimerization increased cleavage efficiency per active monomer. In addition, we mapped a network of critical residues bridging the two active sites and probed this network through engineered mutations. By dissecting the cooperativity and communication between the active sites, we provide insights into the M reaction cycle and functional significance of its dimeric architecture.

PubMed: 41544157
DOI: 10.1126/sciadv.aeb0769

実験手法

X-RAY DIFFRACTION (2.13 Å)