4RNA

Crystal structure of PLpro from Middle East Respiratory Syndrome (MERS) coronavirus

Summary for 4RNA

• Entry DOI: 10.2210/pdb4rna/pdb
• Related: 4PT5
• Descriptor: papain-like protease, ZINC ION, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: mers, coronavirus, papain-like protease, plpro, hydrolase
• Biological source: Human betacoronavirus 2c EMC/2012
• Cellular location: Host cytoplasm, host perinuclear region . Host membrane ; Multi-pass membrane protein : K4LC41
• Total number of polymer chains: 1
• Total formula weight: 36496.75

Authors

Lei, H.,Santarsiero, B.D.,Lee, H.,Johnson, M.E. (deposition date: 2014-10-23, release date: 2015-03-25, Last modification date: 2023-12-06)

Primary citation

Lee, H.,Lei, H.,Santarsiero, B.D.,Gatuz, J.L.,Cao, S.,Rice, A.J.,Patel, K.,Szypulinski, M.Z.,Ojeda, I.,Ghosh, A.K.,Johnson, M.E.
Inhibitor Recognition Specificity of MERS-CoV Papain-like Protease May Differ from That of SARS-CoV.
Acs Chem.Biol., 10:1456-1465, 2015

PubMed Abstract: The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS-CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making critical binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compound acts as a competitive inhibitor with an IC50 of 6 μM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 μM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addition, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3).

PubMed: 25746232
DOI: 10.1021/cb500917m

Experimental method

X-RAY DIFFRACTION (1.794 Å)