8FBZ

Crystal Structure of apo human Glutathione Synthetase Y270E

8FBZ の概要

• エントリーDOI: 10.2210/pdb8fbz/pdb
• 分子名称: Glutathione synthetase, SULFATE ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: glutathione synthesis atpase, biosynthetic protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106052.14

構造登録者

Stanford, S.M.,Santelli, E.,Sankaran, B.,Murali, R.,Bottini, N. (登録日: 2022-11-30, 公開日: 2024-05-08)

主引用文献

Stanford, S.M.,Nguyen, T.P.,Chang, J.,Zhao, Z.,Hackman, G.L.,Santelli, E.,Sanders, C.M.,Katiki, M.,Dondossola, E.,Brauer, B.L.,Diaz, M.A.,Zhan, Y.,Ramsey, S.H.,Watson, P.A.,Sankaran, B.,Paindelli, C.,Parietti, V.,Mikos, A.G.,Lodi, A.,Bagrodia, A.,Elliott, A.,McKay, R.R.,Murali, R.,Tiziani, S.,Kettenbach, A.N.,Bottini, N.
Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy.
Sci Adv, 10:eadg7887-eadg7887, 2024

PubMed Abstract: Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the gene-is overexpressed in prostate tumors. We found up-regulated in human prostate tumors and expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.

PubMed: 38295166
DOI: 10.1126/sciadv.adg7887

実験手法

X-RAY DIFFRACTION (1.59 Å)