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X-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitorX-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitor
Structural highlights
Publication Abstract from PubMedAll coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the beta-CoV subgroup, require the proteolytic activity of nsp5 protease (aka 3C-like protease, 3CLpro) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CLpro from other beta-CoV 2c members including HKU4 and HKU5, MERS-CoV 3CLpro is less efficient at processing a peptide substrate due to MERS-CoV 3CLpro being a weakly associated dimer. Conversely, HKU4, HKU5 and SARS-CoV 3CLpro enzymes are tightly associated dimers. AUC studies support that MERS-CoV 3CLpro is a weakly associated dimer (Kd ~ 52 mu) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CLpro were synthesized and utilized in AUC experiments and demonstrate that MERS-CoV 3CLpro undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at low compound concentration as a result of induced dimerization. Primary sequence comparisons and X-ray structural analyses of two MERS-CoV 3CLpro-inhibitor complexes, determined to 1.6 A, reveal remarkable structural similarity of the dimer interface with 3CLpro from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long-range interactions by the non-conserved amino acids distant from the dimer interface may control MERS-CoV 3CLpro dimerization. Activation of MERS-CoV 3CLpro through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CLpro inhibitors as antiviral agents. Ligand-induced dimerization of MERS coronavirus nsp5 protease (3CLpro): implications for nsp5 regulation and the development of antivirals.,Tomar S, Johnston ML, St John SE, Osswald HL, Nyalapatla PR, Paul LN, Ghosh AK, Denison MR, Mesecar AD J Biol Chem. 2015 Jun 8. pii: jbc.M115.651463. PMID:26055715[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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