{
  "abstract": "Phosphatidylinositol 3-kinase-related kinases (PIKKs), including ATM, ATR, DNA-PKcs, SMG1, TRRAP and mTOR, are regulators of gene expression, DNA damage response and metabolism. Their maturation depends on R2TP, a co-chaperone complex comprising the RUVBL1/2 AAA+ ATPase, RPAP3 and PIH1D1. While small-molecule RUVBL1/2 inhibitors have shown promise in cancer models, the presence of RUVBL1/2 in other complexes raises concerns about specificity. Here, we identified the RUVBL1/2-RPAP3 interface as a vulnerability, exploiting it using de novo designed protein binders that occupy the RPAP3-binding site. These subnanomolar-affinity binders dismantle R2TP, depleting levels of all PIKKs while sparing other RUVBL1/2-containing complexes, including chromatin remodelers INO80, SRCAP and TIP60. CryoEM, proteomic, biochemical and cellular analyses revealed that these binders outcompete RPAP3, trapping RUVBL1/2 in a catalytically inactive conformation. Our findings establish selective disruption of R2TP by artificial proteins as a strategy to control PIKK abundance.",
  "abstract_shown": true,
  "affiliations": [
    "Spanish National Cancer Research Centre (CNIO), Structural Biology Programme, Melchor Fernandez Almagro 3, 28029 Madrid, Spain"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "N. Gonzalez-Rodriguez"
    },
    {
      "name": "A. Lopez-Perrote"
    },
    {
      "name": "C. Reglero"
    },
    {
      "name": "J. Alegrio-Louro"
    },
    {
      "name": "M. Failde-Soler"
    },
    {
      "name": "C. Chacon-Sanchez"
    },
    {
      "name": "E. Blanco-Romero"
    },
    {
      "name": "E. Casajus-Pelegay"
    },
    {
      "name": "G. Lopez-Pernas"
    },
    {
      "name": "I. Hernandez"
    },
    {
      "name": "M. Murga"
    },
    {
      "name": "O. Fernandez-Capetillo"
    },
    {
      "affs": [
        0
      ],
      "name": "O. Llorca"
    },
    {
      "name": "R. Fernandez-Leiro"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8ept63w53gvwj.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.761954",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761954v1.full",
  "id": "8ept63w53gvwj",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761954v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "molecular biology"
    ],
    [
      "openalex",
      "1312|Heat shock proteins research"
    ]
  ],
  "openalex": "W7224078872",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761954v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8ept63w53gvwj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:08Z",
      "native_id": "10.64898/2026.10.26.761954",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761954v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:molecular biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Disruption of R2TP-mediated PIKK maturation with de novo designed binders",
  "title_text": "Disruption of R2TP-mediated PIKK maturation with de novo designed binders",
  "type": "preprint",
  "updated_at": "2026-10-30T12:30:08Z",
  "url": "https://research.draconitic.com/paper/8ept63w53gvwj",
  "venue": "bioRxiv",
  "versions": []
}