Modeling of the Enzyme—Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1

Modeling of the Enzyme—Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1

Poly(ADP-ribose) polymerase 1 (PARP-1) is a key DNA repair enzyme and an important target in cancer treatment. Conventional methods of studying the reaction mechanism of PARP-1 have limitations because of the complex structure of PARP-1 substrates; however, the necessary data can be obtained by mole...

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Bibliographic Details
Published in:Biochemistry (Moscow) Vol. 85; no. 1; pp. 99 - 107
Main Authors: Nilov, D. K., Pushkarev, S. V., Gushchina, I. V., Manasaryan, G. A., Kirsanov, K. I., Švedas, V. K.
Format: Journal Article
Language:English
Published: Moscow Pleiades Publishing 2020
Springer
Springer Nature B.V
Subjects:
Adenosine diphosphate
ADP-ribosylation
Analysis
Binding Sites
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Cancer
Care and treatment
DNA polymerases
DNA repair
Enzymes
Humans
Life Sciences
Methylguanine
Microbiology
Modelling
Molecular docking
Molecular Docking Simulation - methods
Molecular dynamics
Molecular modelling
NAD
Poly (ADP-Ribose) Polymerase-1 - chemistry
Poly Adenosine Diphosphate Ribose - chemistry
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - chemistry
Polymers
Reaction mechanisms
Ribose
Ribosylation
Substrate Specificity
Substrates
Substrates (Biochemistry)
Russia
substrates
docking
inhibitors
molecular dynamics
DNA repair
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Summary:Poly(ADP-ribose) polymerase 1 (PARP-1) is a key DNA repair enzyme and an important target in cancer treatment. Conventional methods of studying the reaction mechanism of PARP-1 have limitations because of the complex structure of PARP-1 substrates; however, the necessary data can be obtained by molecular modeling. In this work, a molecular dynamics model for the PARP-1 enzyme-substrate complex containing NAD + molecule and the end of the poly(ADP-ribose) chain in the form of ADP molecule was obtained for the first time. Interactions with the active site residues have been characterized where Gly863, Lys903, Glu988 play a crucial role, and the S N 1-like mechanism for the enzymatic ADP-ribosylation reaction has been proposed. Models of PARP-1 complexes with more sophisticated two-unit fragments of the growing polymer chain as well as competitive inhibitors 3-aminobenzamide and 7-methylguanine have been obtained by molecular docking.
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ISSN:0006-2979
1608-3040
DOI:10.1134/S0006297920010095