8FBZ

Crystal Structure of apo human Glutathione Synthetase Y270E

Summary for 8FBZ

• Entry DOI: 10.2210/pdb8fbz/pdb
• Descriptor: Glutathione synthetase, SULFATE ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: glutathione synthesis atpase, biosynthetic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 106052.14

Authors

Stanford, S.M.,Santelli, E.,Sankaran, B.,Murali, R.,Bottini, N. (deposition date: 2022-11-30, release date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.59 Å)