View source for 9prp


==N-terminal domain of E. coli MutL bound to NP660==
<StructureSection load='9prp' size='340' side='right'caption='[[9prp]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9prp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9PRP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PRP 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]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CKR:5-cyclopentyloxybenzene-1,3-diol'>A1CKR</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=9prp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9prp OCA], [https://pdbe.org/9prp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9prp RCSB], [https://www.ebi.ac.uk/pdbsum/9prp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9prp ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MUTL_ECOLI MUTL_ECOLI] This protein is involved in the repair of mismatches in DNA. It is required for dam-dependent methyl-directed DNA mismatch repair. May act as a "molecular matchmaker", a protein that promotes the formation of a stable complex between two or more DNA-binding proteins in an ATP-dependent manner without itself being part of the final effector complex. The ATPase activity of MutL is stimulated by DNA.
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== Publication Abstract from PubMed ==
DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutational burden (TMB), microsatellite instability (MSI) and are eligible for checkpoint inhibitor (CPI) immunotherapy which commonly elicits durable responses. We reasoned that pharmacological blockade of MMR could broaden the patient population eligible for immunotherapy. Here we reveal MMR protein PMS2 as a druggable target and describe the discovery and characterisation of first-in-class small molecule MMR pathway modulator NP1867. In vitro treatment of murine cancer cells abrogates MMR function and elicits an MMR-d genotype including increased TMB, MMR-d mutational signatures, and MSI-High (MSI- H) status. Inoculation of syngeneic immunocompetent mice with cancer cells pretreated with NP1867 leads to CPI sensitivity, tumour growth delay, and complete responses. For the first time, we demonstrate pharmacological targeting of MMR to proactively rewire the tumour-host relationship for therapeutic purposes.

Pharmacological inhibition of PMS2 induces MMR deficiency and response to immune checkpoint blockade.,Blagg J, Riou P, Hervieu A, Piumatti E, Rodriguez-Plata MT, Battuello P, Peall A, Amodio V, Vitiello PP, Nightingale DJH, Bago R, Tongue P, Slater T, Parmar K, Patel P, Rodriguez Gonzalez J, Clark DE, Langley GW, Nichols C, Guarne A, Winship PCM, Baker M, Drysdale M, Germano G, Bardelli A Cancer Discov. 2026 Apr 21. doi: 10.1158/2159-8290.CD-26-0003. PMID:42013405<ref>PMID:42013405</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9prp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Blagg J]]
[[Category: Guarne A]]
[[Category: Rodriguez Gonzalez J]]