Molecular dynamics studies of caspase-3

Autoren

M Sulpizi
U Rothlisberger
P Carloni

DOI

10.1016/s0006-3495(03)75026-7

ISSN

0006-3495

Ausgabe der Veröffentlichung

4

Zeitschrift

Biophysical Journal

Sprache

en

Paginierung

2207 - 2215

Datum der Veröffentlichung

2003

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/s0006-3495(03)75026-7

Datum der Datenerfassung

2023

Titel

Molecular Dynamics Studies of Caspase-3

Ausgabe der Zeitschrift

84

Data source: Crossref

Abstract

Caspase-3 is a fundamental target for pharmaceutical interventions against a variety of diseases involving disregulated apoptosis. The enzyme is active as a dimer with two symmetry-related active sites, each featuring a Cys-His catalytic dyad and a selectivity loop, which recognizes the characteristic DEVD pattern of the substrate. Here, a molecular dynamics study of the enzyme in complex with two pentapeptide substrates DEVDG is presented, which provides a characterization of the dynamic properties of the active form in aqueous solution. The mobility of the substrate and that of the catalytic residues are rather low indicating a distinct preorganization effect of the Michaelis complex. An essential mode analysis permits us to identify coupled motions between the two monomers. In particular, it is found that the motions of the two active site loops are correlated and tend to steer the substrate toward the reactive center, suggesting that dimerization has a distinct effect on the dynamic properties of the active site regions. The selectivity loop of one monomer turns out to be correlated with the N-terminal region of the p12 subunit of the other monomer, an interaction that is also found to play a fundamental role in the electrostatic stabilization of the quaternary structure. To further characterize the specific influence of dimerization on the enzyme essential motions, a molecular dynamics analysis is also performed on the isolated monomer.

Addresses

Laboratory of Computational Chemistry and Biochemistry, Federal Institute of Technology (EPFL) CH-1015 Lausanne, Switzerland.

Autoren

M Sulpizi
U Rothlisberger
P Carloni

DOI

10.1016/s0006-3495(03)75026-7

eISSN

1542-0086

Externe Identifier

PubMed Identifier: 12668429
PubMed Central ID: PMC1302787

Open access

false

ISSN

0006-3495

Ausgabe der Veröffentlichung

4

Zeitschrift

Biophysical journal

Schlüsselwörter

Macromolecular Substances
Caspases
Oligopeptides
Cysteine Proteinase Inhibitors
Crystallography
Enzyme Stability
Binding Sites
Enzyme Activation
Protein Conformation
Protein Structure, Tertiary
Protein Binding
Structure-Activity Relationship
Dimerization
Motion
Models, Molecular
Computer Simulation
Caspase 3
Static Electricity
Caspase Inhibitors

Sprache

eng

Medium

Print

Paginierung

2207 - 2215

Datum der Veröffentlichung

2003

Status

Published

Datum der Datenerfassung

2003

Titel

Molecular dynamics studies of caspase-3.

Sub types

Comparative Study
research-article
Evaluation Study
Journal Article

Ausgabe der Zeitschrift

84

Files

http://www.cell.com/article/S0006349503750267/pdf https://europepmc.org/articles/PMC1302787?pdf=render

Data source: Europe PubMed Central

Abstract

Caspase-3 is a fundamental target for pharmaceutical interventions against a variety of diseases involving disregulated apoptosis. The enzyme is active as a dimer with two symmetry-related active sites, each featuring a Cys-His catalytic dyad and a selectivity loop, which recognizes the characteristic DEVD pattern of the substrate. Here, a molecular dynamics study of the enzyme in complex with two pentapeptide substrates DEVDG is presented, which provides a characterization of the dynamic properties of the active form in aqueous solution. The mobility of the substrate and that of the catalytic residues are rather low indicating a distinct preorganization effect of the Michaelis complex. An essential mode analysis permits us to identify coupled motions between the two monomers. In particular, it is found that the motions of the two active site loops are correlated and tend to steer the substrate toward the reactive center, suggesting that dimerization has a distinct effect on the dynamic properties of the active site regions. The selectivity loop of one monomer turns out to be correlated with the N-terminal region of the p12 subunit of the other monomer, an interaction that is also found to play a fundamental role in the electrostatic stabilization of the quaternary structure. To further characterize the specific influence of dimerization on the enzyme essential motions, a molecular dynamics analysis is also performed on the isolated monomer.

Autoren

M Sulpizi
U Rothlisberger
P Carloni

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/12668429

DOI

10.1016/S0006-3495(03)75026-7

Externe Identifier

PubMed Central ID: PMC1302787

ISSN

0006-3495

Ausgabe der Veröffentlichung

4

Zeitschrift

Biophys J

Schlüsselwörter

Binding Sites
Caspase 3
Caspase Inhibitors
Caspases
Computer Simulation
Crystallography
Cysteine Proteinase Inhibitors
Dimerization
Enzyme Activation
Enzyme Stability
Macromolecular Substances
Models, Molecular
Motion
Oligopeptides
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Static Electricity
Structure-Activity Relationship

Sprache

eng

Country

United States

Paginierung

2207 - 2215

PII

S0006-3495(03)75026-7

Datum der Veröffentlichung

2003

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2003

Titel

Molecular dynamics studies of caspase-3.

Sub types

Comparative Study
Evaluation Study
Journal Article

Ausgabe der Zeitschrift

84

Data source: PubMed

Files

Tools