ABSTRACT
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.
Subject(s)
Poly (ADP-Ribose) Polymerase-1/chemistry , Poly Adenosine Diphosphate Ribose/chemistry , Binding Sites , Humans , Molecular Docking Simulation/methods , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Substrate SpecificitySubject(s)
Breast Neoplasms/diagnosis , Breast , Carcinoma, Intraductal, Noninfiltrating/diagnosis , Palpation , Adult , Biopsy, Needle , Breast/pathology , Breast Neoplasms/surgery , Carcinoma, Intraductal, Noninfiltrating/surgery , Female , Humans , Mammography , Mastectomy, Radical , Mastectomy, Segmental , ReoperationABSTRACT
The report is concerned with comparison of the effectiveness of surgery for breast tumors (stage III) after Halsted and Patey. The 5-year survival rates, relapse and tumor dissemination proved nearly identical in both study groups. A modified procedure of radical mastectomy after Patey was used for treatment of stage III breast tumors which did not extend through the underlying tissues of the chest wall.
