6DDK

Crystal structure of the double mutant (D52N/R367Q) of the full-length NT5C2 in the basal state

Summary for 6DDK

• Entry DOI: 10.2210/pdb6ddk/pdb
• Descriptor: Cytosolic purine 5'-nucleotidase, PHOSPHATE ION (3 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 134043.29

Authors

Forouhar, F.,Dieck, C.L.,Tzoneva, G.,Carpenter, Z.,Ambesi-Impiombato, A.,Sanchez-Martin, M.,Kirschner-Schwabe, R.,Lew, S.,Seetharaman, J.,Ferrando, A.A.,Tong, L. (deposition date: 2018-05-10, release date: 2018-07-04, Last modification date: 2023-10-11)

Primary citation

Dieck, C.L.,Tzoneva, G.,Forouhar, F.,Carpenter, Z.,Ambesi-Impiombato, A.,Sanchez-Martin, M.,Kirschner-Schwabe, R.,Lew, S.,Seetharaman, J.,Tong, L.,Ferrando, A.A.
Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.
Cancer Cell, 34:136-147.e6, 2018

PubMed Abstract: 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.

PubMed: 29990496
DOI: 10.1016/j.ccell.2018.06.003

Experimental method

X-RAY DIFFRACTION (2.5 Å)