5ngs

From Proteopedia

(Difference between revisions)

Revision as of 09:10, 4 October 2017

Crystal structure of human MTH1 in complex with inhibitor 6-[(2-phenylethyl)sulfanyl]-7H-purin-2-amine

Structural highlights

5ngs is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5ngr, 5ngt
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[8ODP_HUMAN] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 muM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.

Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space.,Rudling A, Gustafsson R, Almlof I, Homan E, Scobie M, Warpman Berglund U, Helleday T, Stenmark P, Carlsson J J Med Chem. 2017 Oct 3. doi: 10.1021/acs.jmedchem.7b01006. PMID:28929756^[6]

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

References

↑ Fujikawa K, Kamiya H, Yakushiji H, Fujii Y, Nakabeppu Y, Kasai H. The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein. J Biol Chem. 1999 Jun 25;274(26):18201-5. PMID:10373420
↑ Fujii Y, Shimokawa H, Sekiguchi M, Nakabeppu Y. Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins. J Biol Chem. 1999 Dec 31;274(53):38251-9. PMID:10608900
↑ Fujikawa K, Kamiya H, Yakushiji H, Nakabeppu Y, Kasai H. Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res. 2001 Jan 15;29(2):449-54. PMID:11139615
↑ Yoshimura D, Sakumi K, Ohno M, Sakai Y, Furuichi M, Iwai S, Nakabeppu Y. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem. 2003 Sep 26;278(39):37965-73. Epub 2003 Jul 10. PMID:12857738 doi:10.1074/jbc.M306201200
↑ Takagi Y, Setoyama D, Ito R, Kamiya H, Yamagata Y, Sekiguchi M. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem. 2012 Jun 15;287(25):21541-9. doi: 10.1074/jbc.M112.363010. Epub 2012, May 3. PMID:22556419 doi:10.1074/jbc.M112.363010
↑ Rudling A, Gustafsson R, Almlof I, Homan E, Scobie M, Warpman Berglund U, Helleday T, Stenmark P, Carlsson J. Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space. J Med Chem. 2017 Oct 3. doi: 10.1021/acs.jmedchem.7b01006. PMID:28929756 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01006

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5ngs is ON HOLD  until Paper Publication
+==Crystal structure of human MTH1 in complex with inhibitor 6-[(2-phenylethyl)sulfanyl]-7H-purin-2-amine==
+<StructureSection load='5ngs' size='340' side='right' caption='[[5ngs]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5ngs]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NGS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NGS FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8WW:6-(2-phenylethylsulfanyl)-7~{H}-purin-2-amine'>8WW</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ngr|5ngr]], [[5ngt|5ngt]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ngs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ngs OCA], [http://pdbe.org/5ngs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ngs RCSB], [http://www.ebi.ac.uk/pdbsum/5ngs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ngs ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN]] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 muM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.
-Authors:
+Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space.,Rudling A, Gustafsson R, Almlof I, Homan E, Scobie M, Warpman Berglund U, Helleday T, Stenmark P, Carlsson J J Med Chem. 2017 Oct 3. doi: 10.1021/acs.jmedchem.7b01006. PMID:28929756<ref>PMID:28929756</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5ngs" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Almlof, I]]
+[[Category: Berglund, U Warpman]]
+[[Category: Carlsson, J]]
+[[Category: Gustafsson, R]]
+[[Category: Helleday, T]]
+[[Category: Homan, E]]
+[[Category: Rudling, A]]
+[[Category: Scobie, M]]
+[[Category: Stenmark, P]]
+[[Category: Fragment]]
+[[Category: Hydrolase]]
+[[Category: Inhibitor]]
+[[Category: Oxidised nucleotide]]

5ngs

From Proteopedia

Revision as of 09:10, 4 October 2017

Crystal structure of human MTH1 in complex with inhibitor 6-[(2-phenylethyl)sulfanyl]-7H-purin-2-amine

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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