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PDBsum entry 6ddc
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References listed in PDB file
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Key reference
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Title
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Structure and mechanisms of nt5c2 mutations driving thiopurine resistance in relapsed lymphoblastic leukemia.
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Authors
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C.L.Dieck,
G.Tzoneva,
F.Forouhar,
Z.Carpenter,
A.Ambesi-Impiombato,
M.Sánchez-Martín,
R.Kirschner-Schwabe,
S.Lew,
J.Seetharaman,
L.Tong,
A.A.Ferrando.
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Ref.
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Cancer Cell, 2018,
34,
136.
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PubMed id
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Abstract
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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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