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5l4z

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Crystal structure of enzyme in purine metabolism

Structural highlights

5l4z is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.84Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

5NTC_HUMAN Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry.^[1]

Function

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.

Publication Abstract from PubMed

BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is one of the main causes of mortality in childhood malignancies. Previous genetic studies demonstrated that chemoresistant ALL is driven by activating mutations in NT5C2, the gene encoding cytosolic 5 -nucleotidase (cN-II). However, molecular mechanisms underlying this hyperactivation are still unknown. Here, we present kinetic and structural properties of cN-II variants that represent 75 % of mutated alleles in patients who experience relapsed ALL (R367Q, R238W and L375F). RESULTS: Enzyme kinetics measurements revealed that the mutants are consitutively active without need for allosteric activators. This shows that hyperactivity is not caused by a direct catalytic effect but rather by misregulation of cN-II. X-ray crystallography combined with mass spectrometry-based techniques demonstrated that this misregulation is driven by structural modulation of the oligomeric interface within the cN-II homotetrameric assembly. These specific conformational changes are shared between the studied variants, despite the relatively random spatial distribution of the mutations. CONCLUSIONS: These findings define a common molecular mechanism for cN-II hyperactivity, which provides a solid basis for targeted therapy of leukemia. Our study highlights the cN-II oligomerization interface as an attractive pharmacological target.

Oligomeric interface modulation causes misregulation of purine 5 -nucleotidase in relapsed leukemia.,Hnizda A, Skerlova J, Fabry M, Pachl P, Sinalova M, Vrzal L, Man P, Novak P, Rezacova P, Veverka V BMC Biol. 2016 Oct 19;14(1):91. PMID:27756303^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-11. doi: 10.1126/science.1247363. PMID:24482476 doi:http://dx.doi.org/10.1126/science.1247363
↑ Hnizda A, Skerlova J, Fabry M, Pachl P, Sinalova M, Vrzal L, Man P, Novak P, Rezacova P, Veverka V. Oligomeric interface modulation causes misregulation of purine 5 -nucleotidase in relapsed leukemia. BMC Biol. 2016 Oct 19;14(1):91. PMID:27756303 doi:http://dx.doi.org/10.1186/s12915-016-0313-y

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5l4z"

Categories: Homo sapiens | Large Structures | Hnizda A | Pachl P | Rezacova P

@@ Line 3: / Line 3: @@
 <StructureSection load='5l4z' size='340' side='right'caption='[[5l4z]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5l4z]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L4Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5L4Z FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5l4z]] is a 1 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=5L4Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L4Z FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.84&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NT5C2, NT5B, NT5CP, PNT5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/5'-nucleotidase 5'-nucleotidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.5 3.1.3.5] </span></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=5l4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l4z OCA], [https://pdbe.org/5l4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l4z RCSB], [https://www.ebi.ac.uk/pdbsum/5l4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l4z ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5l4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l4z OCA], [http://pdbe.org/5l4z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l4z RCSB], [http://www.ebi.ac.uk/pdbsum/5l4z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l4z ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://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>
+[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 ==
-[[http://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.
+[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 ==
@@ Line 26: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: 5'-nucleotidase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Hnizda, A]]
+[[Category: Hnizda A]]
-[[Category: Pachl, P]]
+[[Category: Pachl P]]
-[[Category: Rezacova, P]]
+[[Category: Rezacova P]]
-[[Category: Enzyme]]
-[[Category: Hydrolase]]
-[[Category: Purine]]

5l4z

From Proteopedia

Current revision

Crystal structure of enzyme in purine metabolism

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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