PDBsum entry 1p76

Hydrolase, virus/viral protein

PDB id: 1p76

Contents

Protein chain

301 a.a.

Ligands

ALA-THR-VAL-ARG-LEU-GLN-ALA

References listed in PDB file

Key reference

Title

Three-Dimensional model of a substrate-Bound sars chymotrypsin-Like cysteine proteinase predicted by multiple molecular dynamics simulations: catalytic efficiency regulated by substrate binding.

Author

Y.P.Pang.

Ref.

Proteins, 2004, 57, 747-757. [DOI no: 10.1002/prot.20249]

PubMed id

15690493

Abstract

Severe acute respiratory syndrome (SARS) is a contagious and deadly disease caused by a new coronavirus. The protein sequence of the chymotrypsin-like cysteine proteinase (CCP) responsible for SARS viral replication has been identified as a target for developing anti-SARS drugs. Here, I report the ATVRLQ(p1)A(p1')-bound CCP 3D model predicted by 420 different molecular dynamics simulations (2.0 ns for each simulation with a 1.0-fs time step). This theoretical model was released at the Protein Data Bank (PDB; code: 1P76) before the release of the first X-ray structure of CCP (PDB code: 1Q2W). In contrast to the catalytic dyad observed in X-ray structures of CCP and other coronavirus cysteine proteinases, a catalytic triad comprising Asp187, His41, and Cys145 is found in the theoretical model of the substrate-bound CCP. The simulations of the CCP complex suggest that substrate binding leads to the displacement of a water molecule entrapped by Asp187 and His41, thus converting the dyad to a more efficient catalytic triad. The CCP complex structure has an expanded active-site pocket that is useful for anti-SARS drug design. In addition, this work demonstrates that multiple molecular dynamics simulations are effective in correcting errors that result from low-sequence-identity homology modeling.

Figure 5.
Figure 5. Different conformations of the catalytic triad in the chymotrypsin-like cysteine proteinase.

Figure 7.
Figure 7. Overlays of the X-ray structure of the substrate-bound chymotrypsin-like cysteine proteinase (yellow) with the corresponding multiple-molecular-dynamics-simulations model (green) and the corresponding SWISS-MODEL model (red) (top: residues 183-185; bottom: residues 151-158).

The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2004, 57, 747-757) copyright 2004.