5fsm: Difference between revisions
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==MTH1 substrate recognition: Complex with a methylbenzimidazolyl acetamide.== | |||
<StructureSection load='5fsm' size='340' side='right'caption='[[5fsm]], [[Resolution|resolution]] 1.67Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5fsm]] 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=5FSM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FSM 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]] 1.67Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=N91:N-(1-METHYLBENZIMIDAZOL-5-YL)ACETAMIDE'>N91</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=5fsm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fsm OCA], [https://pdbe.org/5fsm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fsm RCSB], [https://www.ebi.ac.uk/pdbsum/5fsm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fsm ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://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 == | |||
MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1. | |||
MTH1 Substrate Recognition--An Example of Specific Promiscuity.,Nissink JW, Bista M, Breed J, Carter N, Embrey K, Read J, Winter-Holt JJ PLoS One. 2016 Mar 21;11(3):e0151154. doi: 10.1371/journal.pone.0151154., eCollection 2016. PMID:26999531<ref>PMID:26999531</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5fsm" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Embrey | *[[7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures|7%2C8-dihydro-8-oxoguanine triphosphatase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: Phillips | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bista M]] | |||
[[Category: Breed J]] | |||
[[Category: Carter N]] | |||
[[Category: Embrey K]] | |||
[[Category: Nissink JWM]] | |||
[[Category: Phillips C]] | |||
[[Category: Read J]] | |||
[[Category: Winter JJ]] | |||
Latest revision as of 16:22, 26 July 2023
MTH1 substrate recognition: Complex with a methylbenzimidazolyl acetamide.MTH1 substrate recognition: Complex with a methylbenzimidazolyl acetamide.
Structural highlights
Function8ODP_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 PubMedMTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1. MTH1 Substrate Recognition--An Example of Specific Promiscuity.,Nissink JW, Bista M, Breed J, Carter N, Embrey K, Read J, Winter-Holt JJ PLoS One. 2016 Mar 21;11(3):e0151154. doi: 10.1371/journal.pone.0151154., eCollection 2016. PMID:26999531[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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