5OPP

Crystal structure of S408R cN-II mutant

Summary for 5OPP

• Entry DOI: 10.2210/pdb5opp/pdb
• Related: 5OPK 5OPL 5OPM 5OPN 5OPO
• Descriptor: Cytosolic purine 5'-nucleotidase, GLYCEROL, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: nucleotidase, relapsed leukemia, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 56604.67

Authors

Hnizda, A.,Pachl, P.,Rezacova, P. (deposition date: 2017-08-10, release date: 2018-06-13, Last modification date: 2024-01-17)

Primary citation

Hnizda, A.,Fabry, M.,Moriyama, T.,Pachl, P.,Kugler, M.,Brinsa, V.,Ascher, D.B.,Carroll, W.L.,Novak, P.,Zaliova, M.,Trka, J.,Rezacova, P.,Yang, J.J.,Veverka, V.
Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation.
Leukemia, 32:1393-1403, 2018

PubMed Abstract: Activating mutations in NT5C2, a gene encoding cytosolic purine 5'-nucleotidase (cN-II), confer chemoresistance in relapsed acute lymphoblastic leukemia. Here we show that all mutants became independent of allosteric effects of ATP and thus constitutively active. Structural mapping of mutations described in patients demonstrates that 90% of leukemia-specific allelles directly affect two regulatory hotspots within the cN-II molecule-the helix A region: residues 355-365, and the intersubunit interface: helix B (232-242) and flexible interhelical loop L (400-418). Furthermore, analysis of hetero-oligomeric complexes combining wild-type (WT) and mutant subunits showed that the activation is transmitted from the mutated to the WT subunit. This intersubunit interaction forms structural basis of hyperactive NT5C2 in drug-resistant leukemia in which heterozygous NT5C2 mutation gave rise to hetero-tetramer mutant and WT proteins. This enabled us to define criteria to aid the prediction of NT5C2 drug resistance mutations in leukemia.

PubMed: 29535428
DOI: 10.1038/s41375-018-0073-5

Experimental method

X-RAY DIFFRACTION (1.7 Å)