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PDBsum entry 2a5i
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the main peptidase from the sars coronavirus inhibited by a substrate-Like aza-Peptide epoxide.
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Authors
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T.W.Lee,
M.M.Cherney,
C.Huitema,
J.Liu,
K.E.James,
J.C.Powers,
L.D.Eltis,
M.N.James.
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Ref.
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J Mol Biol, 2005,
353,
1137-1151.
[DOI no: ]
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PubMed id
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Abstract
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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).
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Figure 3.
Figure 3. Binding of APE (orange) in the substrate-binding
regions of SARS-CoV Mpro. (a) Stereo view of the outstanding
density in the F[o] -F[c] map for the structures of the Mpro:APE
complex and protomer B of the Click to view the MathML source-
[0?wchp=dGLbVlz-zSkWA]
complex. (b) The corresponding stereo view for protomer A of the
Click to view the MathML source- [0?wchp=dGLbVlz-zSkWA]
complex.
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Figure 7.
Figure 7. Models for each of the four diastereomers of
Cbz-Leu-Phe-AGln-EP-COOEt binding to SARS-CoV Mpro before the
nucleophilic attack by the Cys145 Sg atom of the peptidase. (a)
2S, 3S, (b) 2R, 3R, (c) 2S, 3R, (d) 2R, 3S.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
353,
1137-1151)
copyright 2005.
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