4YLU

X-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitor

Summary for 4YLU

• Entry DOI: 10.2210/pdb4ylu/pdb
• Related: 4RSP
• Descriptor: ORF1a protein, N-{4-[(1H-benzotriazol-1-ylacetyl)(thiophen-3-ylmethyl)amino]phenyl}propanamide, ACETATE ION, ... (4 entities in total)
• Functional Keywords: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Middle East respiratory syndrome coronavirus
• Total number of polymer chains: 4
• Total formula weight: 135448.95

Authors

Tomar, S.,Mesecar, A.D. (deposition date: 2015-03-05, release date: 2015-06-17, Last modification date: 2024-02-28)

Primary citation

Tomar, S.,Johnston, M.L.,St John, S.E.,Osswald, H.L.,Nyalapatla, P.R.,Paul, L.N.,Ghosh, A.K.,Denison, M.R.,Mesecar, A.D.
Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS.
J.Biol.Chem., 290:19403-19422, 2015

PubMed Abstract: All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the β-CoV subgroup, require the proteolytic activity of the nsp5 protease (also known as 3C-like protease, 3CL(pro)) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CL(pro) from other β-CoV 2c members, including HKU4 and HKU5, MERS-CoV 3CL(pro) is less efficient at processing a peptide substrate due to MERS-CoV 3CL(pro) being a weakly associated dimer. Conversely, HKU4, HKU5, and SARS-CoV 3CL(pro) enzymes are tightly associated dimers. Analytical ultracentrifugation studies support that MERS-CoV 3CL(pro) is a weakly associated dimer (Kd ∼52 μm) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CL(pro) were synthesized and utilized in analytical ultracentrifugation experiments and demonstrate that MERS-CoV 3CL(pro) undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at a low compound concentration as a result of induced dimerization. Primary sequence comparisons and x-ray structural analyses of two MERS-CoV 3CLpro and inhibitor complexes, determined to 1.6 Å, reveal remarkable structural similarity of the dimer interface with 3CL(pro) from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long range interactions by the nonconserved amino acids distant from the dimer interface may control MERS-CoV 3CL(pro) dimerization. Activation of MERS-CoV 3CL(pro) through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CL(pro) inhibitors as antiviral agents.

PubMed: 26055715
DOI: 10.1074/jbc.M115.651463

Experimental method

X-RAY DIFFRACTION (2.1 Å)