{
  "abstract": "The Rho GTPase RhoJ is a key regulator of tumour angiogenesis and has been identified as a target for anti-angiogenic drug design. Its high sequence conservation with the related Rho GTPase Cdc42 complicates selective drug discovery. RhoJ has a unique N-terminal extension (Asn2-Lys19) that is absent in Cdc42 and other Rho GTPases. Here, we use molecular dynamics simulations to identify a novel allosteric pocket formed by the RhoJ N-terminus and show that this pocket contributes to interactions with key downstream signalling partners. Structure-based virtual screening of small molecules targeting this pocket identified the antifungal terconazole as a potential binder. Computational docking revealed that terconazole occupies the N-terminal pocket, sharing critical contacts with the interface between RhoJ and PAK3, a key interacting partner. To validate this, we developed an optimized bioluminescence resonance energy transfer (eBRET2)-based biosensor to monitor the interaction between RhoJ and PAK3 in live cells and saw that terconazole disrupted the RhoJ:PAK3 interaction in a dose-dependent manner. Together, our MD results show that the RhoJ N-terminal extension assumes structure on binding to PAK3 and contributes to that interaction, while our cellular biosensor data support targeting this pocket to modulate the RhoJ:PAK3 interaction. The ability of terconazole to bind to the N-terminal pocket and disrupt PAK3 binding provides proof of concept for the specific targeting of RhoJ in the development of novel anti-angiogenic drugs.",
  "abstract_shown": true,
  "affiliations": [
    "School of Biochemistry and Biomedical Sciences, University of Bristol"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "W. Chen"
    },
    {
      "name": "D. K. Shoemark"
    },
    {
      "name": "R. A. Corey"
    },
    {
      "name": "T. N. Adrienko"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Mellor"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c5qnetbx9s0qr.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.14.758331",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.758331v1.full",
  "id": "c5qnetbx9s0qr",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.758331v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biochemistry"
    ],
    [
      "openalex",
      "1312|Protein Kinase Regulation and GTPase Signaling"
    ]
  ],
  "openalex": "W7222427698",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.14.758331v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c5qnetbx9s0qr.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:05Z",
      "native_id": "10.64898/2026.10.14.758331",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.14.758331v2"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Kinase Regulation and GTPase Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Identification and targeting of a novel drug pocket in the tumour angiogenesis regulator RhoJ",
  "title_text": "Identification and targeting of a novel drug pocket in the tumour angiogenesis regulator RhoJ",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:50Z",
  "url": "https://research.draconitic.com/paper/c5qnetbx9s0qr",
  "venue": "bioRxiv",
  "versions": []
}