Modeling of the Enzyme-Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1
| Autor: | D. K. Nilov, Sergey Pushkarev, G. A. Manasaryan, Vytas K. Švedas, I. V. Gushchina, K. I. Kirsanov |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Reaction mechanism Poly Adenosine Diphosphate Ribose Binding Sites biology Molecular model Chemistry Stereochemistry Poly ADP ribose polymerase 030302 biochemistry & molecular biology Poly (ADP-Ribose) Polymerase-1 Active site Substrate (chemistry) General Medicine Poly(ADP-ribose) Polymerase Inhibitors Biochemistry Substrate Specificity Molecular Docking Simulation 03 medical and health sciences Enzyme biology.protein Humans NAD+ kinase Polymerase |
| Zdroj: | Biochemistry. Biokhimiia. 85(1) |
| ISSN: | 1608-3040 |
| Popis: | 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 SN1-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. |
| Databáze: | OpenAIRE |
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