5H08

Human PTPRZ D1 domain complexed with NAZ2329

Summary for 5H08

• Entry DOI: 10.2210/pdb5h08/pdb
• Related: 5AWX
• Descriptor: Receptor-type tyrosine-protein phosphatase zeta, 3-{[2-Ethoxy-5-(trifluoromethyl)benzyl]sulfanyl}-N-(phenylsulfonyl)thiophene-2-carboxamide (3 entities in total)
• Functional Keywords: protein tyrosine phosphatase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted : P23471
• Total number of polymer chains: 1
• Total formula weight: 34455.96

Authors

Sugawara, H. (deposition date: 2016-10-04, release date: 2017-07-26, Last modification date: 2023-11-08)

Primary citation

Fujikawa, A.,Sugawara, H.,Tanaka, T.,Matsumoto, M.,Kuboyama, K.,Suzuki, R.,Tanga, N.,Ogata, A.,Masumura, M.,Noda, M.
Targeting PTPRZ inhibits stem cell-like properties and tumorigenicity in glioblastoma cells
Sci Rep, 7:5609-5609, 2017

PubMed Abstract: The R5 subfamily of receptor-type protein tyrosine phosphatases (RPTPs) comprises PTPRZ and PTPRG. A recent study on primary human glioblastomas suggested a close association between PTPRZ1 (human PTPRZ) expression and cancer stemness. However, the functional roles of PTPRZ activity in glioma stem cells have remained unclear. In the present study, we found that sphere-forming cells from the rat C6 and human U251 glioblastoma cell lines showed high expression levels of PTPRZ-B, the short receptor isoform of PTPRZ. Stable PTPRZ knockdown altered the expression levels of stem cell transcription factors such as SOX2, OLIG2, and POU3F2 and decreased the sphere-forming abilities of these cells. Suppressive effects on the cancer stem-like properties of the cells were also observed following the knockdown of PTPRG. Here, we identified NAZ2329, a cell-permeable small molecule that allosterically inhibits both PTPRZ and PTPRG. NAZ2329 reduced the expression of SOX2 in C6 and U251 cells and abrogated the sphere-forming abilities of these cells. Tumor growth in the C6 xenograft mouse model was significantly slower with the co-treatment of NAZ2329 with temozolomide, an alkylating agent, than with the individual treatments. These results indicate that pharmacological inhibition of R5 RPTPs is a promising strategy for the treatment of malignant gliomas.

PubMed: 28717188
DOI: 10.1038/s41598-017-05931-8

Experimental method

X-RAY DIFFRACTION (2.53 Å)