View source for 6ddb


==Crystal structure of the double mutant (D52N/R367Q) of NT5C2-537X in the basal state, Northeast Structural Genomics Consortium Target==
<StructureSection load='6ddb' size='340' side='right'caption='[[6ddb]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ddb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DDB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ddb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ddb OCA], [https://pdbe.org/6ddb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ddb RCSB], [https://www.ebi.ac.uk/pdbsum/6ddb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ddb ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/5NTC_HUMAN 5NTC_HUMAN] Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:24482476</ref> 
== Function ==
[https://www.uniprot.org/uniprot/5NTC_HUMAN 5NTC_HUMAN] May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5'-monophosphate (IMP) and other purine nucleotides.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.,Dieck CL, Tzoneva G, Forouhar F, Carpenter Z, Ambesi-Impiombato A, Sanchez-Martin M, Kirschner-Schwabe R, Lew S, Seetharaman J, Tong L, Ferrando AA Cancer Cell. 2018 Jul 9;34(1):136-147.e6. doi: 10.1016/j.ccell.2018.06.003. PMID:29990496<ref>PMID:29990496</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ddb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ambesi-Impiombato A]]
[[Category: Carpenter Z]]
[[Category: Dieck CL]]
[[Category: Ferrando AA]]
[[Category: Forouhar F]]
[[Category: Kirschner-Schwabe R]]
[[Category: Lew S]]
[[Category: Sanchez-Martin M]]
[[Category: Seetharaman J]]
[[Category: Tong L]]
[[Category: Tzoneva G]]