2. Academic Validation
  3. Crystal structures of the catalytic domain of human PARP15 in complex with small molecule inhibitors

Crystal structures of the catalytic domain of human PARP15 in complex with small molecule inhibitors

  • Biochem Biophys Res Commun. 2022 Sep 24:622:93-100. doi: 10.1016/j.bbrc.2022.06.070.
Xuelan Zhou 1,  Yang Yang 2,  Qin Xu 3,  Huan Zhou 3,  Fanglin Zhong 4,  Jun Deng 5,  Jin Zhang 6,  Jian Li 7
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou, 341000, China.
  • 2 Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen, 518118, China.
  • 3 Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China.
  • 4 Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen, 518118, China; Jiangxi Jmerry Biopharmaceutical Co., Ltd, Ganzhou, 341000, China.
  • 5 The First Affiliated Hospital of Nanchang University, Nanchang, 330031, Jiangxi, China.
  • 6 Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen, 518118, China; Jiangxi Jmerry Biopharmaceutical Co., Ltd, Ganzhou, 341000, China. Electronic address: [email protected].
  • 7 College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou, 341000, China. Electronic address: [email protected].
PMID: 35843099 DOI: 10.1016/j.bbrc.2022.06.070
Abstract

PARP15, or ARTD7, is an enzyme carrying out mono-ADP-ribosylation and regulating activities of a range of cellular proteins. This enzyme belongs to the family of the poly(ADP-ribose) polymerases (PARPs), which comprises of proteins with various potential disease indications. Due to their involvement in a number of cellular processes and important role in DNA repair and regulation, PARPs have been considered attractive therapeutic targets over the past few years. The pursuit of small molecule PARP inhibitors has resulted in several FDA approved drugs for multiple cancers so far. As the use of PARP inhibitors as drug scaffolds is actively explored recently, there is increasing interest in the design of selective inhibitors based on the structural features of the PARP proteins. Here, we solved high-resolution crystal structures of the human PARP15 catalytic domain in complex with three marketed drugs of PARP inhibitors, which includes compounds 3-AB, iniparib and niraparib. The structures reported here contribute to our understanding of the ligand binding modes and structural features in the PARP15 catalytic domain, which can be employed to guide the rational design of selective inhibitors of PARPs.

Keywords

Cancer; PARP15; Poly(ADP-Ribose) polymerase; Structural biology; Structure-based drug discovery.

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