期刊
CANCER CELL
卷 34, 期 1, 页码 136-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.06.003
关键词
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资金
- Leukemia & Lymphoma Society [TRP2181-14]
- NIH [CA206501, P30CA013696, S10OD012018]
- Protein Structure Initiative of the NIH [U54 GM074958]
- Alex Lemonade Stand Foundation
- Howard Hughes Medical Institute International Student Research Fellowship
- Rally Foundation Fellowship
- NIH/National Cancer Institute [T32-CA09503]
- Life Science Biomedical Technology Research, National Synchrotron Light Source II and Structural Molecular Group at Stanford Synchrotron Radiation Lightsource under National Institute of General Medical Sciences [P41GM111244, P41GM103393]
- Department of Energy Biological and Environmental Research [DE-SC0012704]
- Department of Energy Basic Energy Sciences [DE-AC02-76SF00515]
- NATIONAL CANCER INSTITUTE [T32CA009503, R35CA210065, P30CA013696, R01CA216981] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103393, P41GM111244, U54GM074958, T32GM008224] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD012018, S10OD021832] Funding Source: NIH RePORTER
Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.
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