4WME

Crystal structure of catalytically inactive MERS-CoV 3CL Protease (C148A) in spacegroup C2

Summary for 4WME

• Entry DOI: 10.2210/pdb4wme/pdb
• Related: 4WMD 4WMF
• Descriptor: MERS-CoV 3CL protease, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: mers, coronavirus, 3cl protease, hydrolase
• Biological source: Middle East respiratory syndrome coronavirus
• Cellular location: Host cytoplasm, host perinuclear region . Host membrane ; Multi-pass membrane protein : W6A941
• Total number of polymer chains: 4
• Total formula weight: 134405.66

Authors

Lountos, G.T.,Needle, D.,Waugh, D.S. (deposition date: 2014-10-08, release date: 2015-05-13, Last modification date: 2023-09-27)

Primary citation

Needle, D.,Lountos, G.T.,Waugh, D.S.
Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity.
Acta Crystallogr.,Sect.D, 71:1102-1111, 2015

PubMed Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus that causes severe respiratory illness accompanied by multi-organ dysfunction, resulting in a case fatality rate of approximately 40%. As found in other coronaviruses, the majority of the positive-stranded RNA MERS-CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain-like protease and at 11 sites by a 3C-like protease (3 CL(pro)). Since 3 CL(pro) is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3 CL(pro) inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS-CoV 3 CL(pro) enzyme were determined. The aim was to co-crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C-terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme-product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS-CoV 3 CL(pro); however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure-based design of small-molecule inhibitors of the MERS-CoV 3 CL(pro) enzyme.

PubMed: 25945576
DOI: 10.1107/S1399004715003521

Experimental method

X-RAY DIFFRACTION (1.55 Å)