8hlr
Human ADP-ribosyltransferase 1 (PARP1) catalytic domain bound to Fluzoparib (SHR3162)
Structural highlights
FunctionPARP1_HUMAN Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production.[1] [2] [3] [4] Publication Abstract from PubMedThe PARP-1/2 inhibitors have been approved for the treatment of cancers by modulating the enzymatic activity and/or the trapping ability for damaged DNA of PARP-1 and/or PARP-2, and the selective PARP-1 inhibitors are now attracting considerable attention with an aim to search for drug candidates with an improved safety. Exploring the structural basis of the selectivity and trapping capability of known PARP-1/2 inhibitors would be beneficial for the discovery of the improved inhibitors. Herein, a mutated PARP-2 catalytic domain, designated as catPARP-2SE, was engineered. It could be expressed in an elevated level and had capability to crystalize at 25 degrees C, which greatly facilitated obtaining PARP-2 crystals. Consequently, the complex structures of Fluzoparib, Pamiparib, Rucaparib, and Niraparib within PARP-2 were achieved. Taking advantage of these complexed structures, the detailed and quantitative analyses of protein-ligand and intra-protein interactions (alphaB-alphaF, alphaJ-alphaB, alphaJ-alphaF, ASL-alphaD and ASL-alphaF interfaces) were conducted with quantum chemistry methods (GFN2-xTB and IGMH). It suggested that the residues adjacent to Asp766 in the HD and ASL domains and the alphaJ-alphaF and ASL-alphaD interfaces were closely related to the selectivity and trapping mechanism. These results would provide some insights for the design and development of novel PARP-1/2 inhibitors with improved pharmacodynamic properties. Engaging an engineered PARP-2 catalytic domain mutant to solve the complex structures harboring approved drugs for structure analyses.,Wang X, Zhou J, Xu B Bioorg Chem. 2025 Jun 15;160:108471. doi: 10.1016/j.bioorg.2025.108471. Epub 2025 , Apr 12. PMID:40228437[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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