2A5K

Crystal structures of SARS coronavirus main peptidase inhibited by an aza-peptide epoxide in space group P212121

Summary for 2A5K

• Entry DOI: 10.2210/pdb2a5k/pdb
• Related: 2A5A 2A5I
• Descriptor: 3C-like peptidase, (5S,8S,14R)-ETHYL 11-(3-AMINO-3-OXOPROPYL)-8-BENZYL-14-HYDROXY-5-ISOBUTYL-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,11-TETRAAZAPENTADECAN-15-OATE (3 entities in total)
• Functional Keywords: cysteine peptidase, 3c-like, n-finger, chymotrypsin-like fold, long loop, alpha-helical domain, dimer, catalytic dyad, specificity pockets, aza-peptide epoxide, substrate-like inhibitor, c-s covalent bond, epoxide stereochemistry, hydrolase
• Biological source: SARS coronavirus
• Cellular location: Non-structural protein 3: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 4: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 6: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 7: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 8: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 9: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 10: Host cytoplasm, host perinuclear region (By similarity). Helicase: Host endoplasmic reticulum-Golgi intermediate compartment (Potential). Uridylate-specific endoribonuclease: Host cytoplasm, host perinuclear region (By similarity): P59641
• Total number of polymer chains: 2
• Total formula weight: 69178.85

Authors

Lee, T.-W.,Cherney, M.M.,Huitema, C.,Liu, J.,James, K.E.,Powers, J.C.,Eltis, L.D.,James, M.N. (deposition date: 2005-06-30, release date: 2005-10-25, Last modification date: 2024-11-13)

Primary citation

Lee, T.-W.,Cherney, M.M.,Huitema, C.,Liu, J.,James, K.E.,Powers, J.C.,Eltis, L.D.,James, M.N.
Crystal Structures of the Main Peptidase from the SARS Coronavirus Inhibited by a Substrate-like Aza-peptide Epoxide
J.Mol.Biol., 353:1137-1151, 2005

PubMed Abstract: The main peptidase (M(pro)) from the coronavirus (CoV) causing severe acute respiratory syndrome (SARS) is one of the most attractive molecular targets for the development of anti-SARS agents. We report the irreversible inhibition of SARS-CoV M(pro) by an aza-peptide epoxide (APE; k(inact)/K(i) = 1900(+/-400) M(-1) s(-1)). The crystal structures of the M(pro):APE complex in the space groups C2 and P2(1)2(1)2(1) revealed the formation of a covalent bond between the catalytic Cys145 S(gamma) atom of the peptidase and the epoxide C3 atom of the inhibitor, substantiating the mode of action of this class of cysteine-peptidase inhibitors. The aza-peptide component of APE binds in the substrate-binding regions of M(pro) in a substrate-like manner, with excellent structural and chemical complementarity. In addition, the crystal structure of unbound M(pro) in the space group C2 revealed that the "N-fingers" (N-terminal residues 1 to 7) of both protomers of M(pro) are well defined and the substrate-binding regions of both protomers are in the catalytically competent conformation at the crystallization pH of 6.5, contrary to the previously determined crystal structures of unbound M(pro) in the space group P2(1).

PubMed: 16219322
DOI: 10.1016/j.jmb.2005.09.004

Experimental method

X-RAY DIFFRACTION (2.3 Å)