6fiu: Difference between revisions

Latest revision as of 12:28, 9 May 2024

Human cytosolic 5'-nucleotidase II soaked with 10mM 2-(6-([1,1'-Biphenyl]-3-carboxamido)-9H-purin-9-yl)acetic acid

Structural highlights

6fiu 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 2.5Å
Ligands:	GOL, MG, SO4
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

The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200muM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.

Lead optimization and biological evaluation of fragment-based cN-II inhibitors.,Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051^[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:https://dx.doi.org/10.1126/science.1247363
↑ Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S. Lead optimization and biological evaluation of fragment-based cN-II inhibitors. Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051 doi:https://dx.doi.org/10.1016/j.ejmech.2019.02.040

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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:https://dx.doi.org/10.1126/science.1247363

[2] Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S. Lead optimization and biological evaluation of fragment-based cN-II inhibitors. Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051 doi:https://dx.doi.org/10.1016/j.ejmech.2019.02.040

[1]

[2]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6fiu is ON HOLD
+==Human cytosolic 5'-nucleotidase II soaked with 10mM 2-(6-([1,1'-Biphenyl]-3-carboxamido)-9H-purin-9-yl)acetic acid==
+<StructureSection load='6fiu' size='340' side='right'caption='[[6fiu]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6fiu]] 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=6FIU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FIU 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]] 2.5&#8491;</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>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6fiu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fiu OCA], [https://pdbe.org/6fiu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fiu RCSB], [https://www.ebi.ac.uk/pdbsum/6fiu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fiu 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 ==
+The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200muM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.
-Authors: Aghajari, N., Preeti, P.
+Lead optimization and biological evaluation of fragment-based cN-II inhibitors.,Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051<ref>PMID:30798051</ref>
-Description: Human cytosolic 5'-nucleotidase II soaked with 10mM 2-(6-([1,1'-Biphenyl]-3-carboxamido)-9H-purin-9-yl)acetic acid
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Preeti, P]]
+<div class="pdbe-citations 6fiu" style="background-color:#fffaf0;"></div>
-[[Category: Aghajari, N]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Aghajari N]]
+[[Category: Preeti P]]

6fiu: Difference between revisions

Latest revision as of 12:28, 9 May 2024

Human cytosolic 5'-nucleotidase II soaked with 10mM 2-(6-([1,1'-Biphenyl]-3-carboxamido)-9H-purin-9-yl)acetic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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