PDBsum entry 1p76

Hydrolase, virus/viral protein

PDB id: 1p76

Contents

Protein chain

301 a.a.

Ligands

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

Theoretical model

PDB id:

1p76

Name:

Hydrolase, virus/viral protein

Title:

3d structure of the substrate-bound sars chymotrypsin-like cysteine proteinase

Structure:

3c-like proteinase. Chain: a. Synonym: chymotrypsin-like cysteine proteinase. Sars substrate. Chain: b

Source:

Human coronavirus. Strain sars. Strain sars

Ensemble:

8 models

Authors:

Y.-P.Pang

Key ref:

Y.P.Pang (2004). Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: catalytic efficiency regulated by substrate binding. Proteins, 57, 747-757. PubMed id: 15690493 DOI: 10.1002/prot.20249

Date:

30-Apr-03 Release date: 01-Jul-03

Protein chain

P59641  (R1AB_CVHSA) -

Enzyme reactions

• Enzyme class: E.C.3.4.24.- - ?????

DOI no: 10.1002/prot.20249

Proteins 57:747-757 (2004)

PubMed id: 15690493

Three-dimensional model of a substrate-bound SARS chymotrypsin-like cysteine proteinase predicted by multiple molecular dynamics simulations: catalytic efficiency regulated by substrate binding.

Y.P.Pang.

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.

Selected figure(s)

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.

Figures were selected by the author.

Author's comment

For the validation of this model (PDB code: 2aj5) see the following reference:
Dooley AJ, Shindo N, Taggart B, Park JG, Pang YP (2006). From genome to drug lead: identification of a small-molecule inhibitor of the SARS virus. Bioorg. Med. Chem. Lett., 16, 830-833. [PubMed: 16325400]