View source for 9xri


==Crystal structure of MTH1 in complex with acoramidis bound at the active site and protein-protein interface (molar ratio 1:24)==
<StructureSection load='9xri' size='340' side='right'caption='[[9xri]], [[Resolution|resolution]] 1.08&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9xri]] 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=9XRI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9XRI 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]] 1.08&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=16V:3-[3-(3,5-DIMETHYL-1H-PYRAZOL-4-YL)PROPOXY]-4-FLUOROBENZOIC+ACID'>16V</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=9xri FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9xri OCA], [https://pdbe.org/9xri PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9xri RCSB], [https://www.ebi.ac.uk/pdbsum/9xri PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9xri 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 ==
Cancer cells experience elevated oxidative stress and rely on MutT Homologue 1 (MTH1) to sanitize the oxidized nucleotide pool and prevent the incorporation of damaged nucleotides into DNA. This dependency has established MTH1 as a promising target for anticancer drug development. Here, we identify acoramidisî¸an approved therapeutic for transthyretin amyloidosisî¸as a previously unrecognized and selective inhibitor of MTH1 through a drug-repositioning strategy. Biochemical analyses demonstrate that acoramidis competitively inhibits MTH1 enzymatic activity with micromolar potency. Thermodynamic measurements reveal that acoramidis binding is characterized by substantial entropic favorability, suggesting a dominant contribution from hydrophobic interactions and conformational adaptability. X-ray crystallography uncovers a ligand-induced expansion of the substrate-binding pocket caused by displacement of the gatekeeper residue Phe27, a structural alteration not observed in the TH287-bound or apo forms. Among the key interactions in the MTH1 active site, hydrogen bonding with residues Asp119 and Asp120 plays a central role in ligand recognition and is also exploited by known inhibitors. However, the pronounced conformational rearrangement induced by acoramidis is unique and likely underlies its distinct thermodynamic signature and moderate binding affinity. Given its well-established clinical safety and pharmacokinetic properties, acoramidis provides an immediately accessible chemical scaffold for further optimization. Overall, this study identifies a clinically approved drug with a novel mechanism of MTH1 inhibition and establishes a foundation for the rational design of next-generation MTH1 inhibitors with improved potency and potential anticancer efficacy.

Identification of Acoramidis as a Repurposed Inhibitor of the DNA Sanitization Enzyme MutT Homologue 1.,Yokoyama T, Nakamura T, Goto M, Kusaka K ACS Pharmacol Transl Sci. 2026 Feb 24;9(3):698-705. doi: , 10.1021/acsptsci.5c00782. eCollection 2026 Mar 13. PMID:41852632<ref>PMID:41852632</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9xri" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Goto M]]
[[Category: Kusaka K]]
[[Category: Nakamura T]]
[[Category: Yokoyama T]]