6XBG

Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAW246

Summary for 6XBG

• Entry DOI: 10.2210/pdb6xbg/pdb
• Related PRD ID: PRD_002392
• Descriptor: 3C-like proteinase, inhibitor UAW246, GLYCEROL, ... (5 entities in total)
• Functional Keywords: covid, covid19, covid-19, sars, sars cov2, cov, ncov 19, coronavirus, main protease, 3cl, mpro, pro, viral protein, gc376, calpain inhibitor ii, leupeptin, calpain, aldehyde, gc-376, 3cl-like, a-ketoamide, uaw41, uaw246, uaw247, uaw248, 246, 247, 248, alpheketoamide, alpha, ketoamide, peptidomimetic, protease, cysteine, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 4
• Total formula weight: 69466.20

Authors

Sacco, M.,Ma, C.,Wang, J.,Chen, Y. (deposition date: 2020-06-05, release date: 2020-06-17, Last modification date: 2024-11-13)

Primary citation

Sacco, M.D.,Ma, C.,Lagarias, P.,Gao, A.,Townsend, J.A.,Meng, X.,Dube, P.,Zhang, X.,Hu, Y.,Kitamura, N.,Hurst, B.,Tarbet, B.,Marty, M.T.,Kolocouris, A.,Xiang, Y.,Chen, Y.,Wang, J.
Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M pro and cathepsin L.
Sci Adv, 6:-, 2020

PubMed Abstract: The main protease (M) of SARS-CoV-2 is a key antiviral drug target. While most M inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several M inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of M in complex with calpain inhibitors II and XII and three analogs of The structure of M with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.

PubMed: 33158912
DOI: 10.1126/sciadv.abe0751

Experimental method

X-RAY DIFFRACTION (1.45 Å)