Cancer Prevention and Research Institute of Texas (CPRIT)
RP220582
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI167967
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI150776
米国
Welch Foundation
I-1948-20240404
米国
Howard Hughes Medical Institute (HHMI)
米国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2025 タイトル: A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site in . 著者: Dylon R Stephens / Ho Yee Joyce Fung / Yan Han / Jue Liang / Zhe Chen / Joseph Ready / James J Collins / 要旨: Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within ...Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within schistosomes. Thus, praziquantel has remained the frontline treatment for schistosomiasis despite known liabilities. Here, we have conducted a genome-wide study in using the human druggable genome as a bioinformatic template to identify essential genes within schistosomes bearing similarity to catalogued drug targets. Then, we assessed these candidate targets in silico using a set of unbiased criteria to determine which possess ideal characteristics for a ready-made drug discovery campaign. Following this prioritization, we pursued a parasite p97 ortholog as a bona-fide drug target for the development of therapeutics to treat schistosomiasis. From this effort, we identified a covalent inhibitor series that kills schistosomes through an on-target killing mechanism by disrupting the ubiquitin proteasome system. Fascinatingly, these inhibitors induce a conformational change in the conserved D2 domain P-loop of schistosome p97 upon modification of Cys519. This conformational change reveals an allosteric binding site adjacent to the D2 domain active site reminiscent of the "DFG" flip in protein kinases. This allosteric binding site can potentially be utilized to generate new classes of species-selective p97 inhibitors. Furthermore, these studies provide a resource for the development of alternative therapeutics for schistosomiasis and a workflow to identify potential drug targets in similar systems with few available molecular tools.
モデルのタイプ: OTHER / 詳細: Ab initio reconstruction with C6 symmetry
最終 再構成
想定した対称性 - 点群: C6 (6回回転対称) / 解像度のタイプ: BY AUTHOR / 解像度: 2.85 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: cryoSPARC 詳細: Homogenous refinement with global CTF refinement and local motion correction. The map was also sharpened by deepEMhancer to obtain final map used for modeling. 使用した粒子像数: 174830
初期 角度割当
タイプ: MAXIMUM LIKELIHOOD / ソフトウェア - 名称: cryoSPARC
最終 角度割当
タイプ: MAXIMUM LIKELIHOOD / ソフトウェア - 名称: cryoSPARC
最終 3次元分類
クラス数: 3 / ソフトウェア - 名称: cryoSPARC 詳細: 3 ab initio models as input model for heterogenous refinement
FSC曲線 (解像度の算出)
-
原子モデル構築 1
詳細
Model built by ModelAngelo for one chain. Other chains were manually fitted in Chimera and merged.
精密化
プロトコル: AB INITIO MODEL
得られたモデル
PDB-9ox9: Cryo-EM structure of S. Mansoni p97 bound to CB-5083