{
  "abstract": "Proteolysis-targeting chimeras (PROTACs) promote targeted protein degradation by inducing a transient ternary complex between a protein of interest and an E3 ubiquitin ligase. Despite the clinical promise of these event-driven therapeutics, defining the conformational landscape and interfacial organization of these complexes remains challenging. Here, we use an integrated native mass spectrometry (nMS) approach combining ion mobility, surface-induced dissociation (SID), and variable-temperature electrospray ionization (vT-ESI) to determine how small-molecule architecture shapes the structural and thermodynamic landscapes of bromodomain-containing protein 4 (BRD4) with the VCB E3 ligase complex. Using a set of PROTACs that differ in targeting ligand identity (JQ1 versus I-BET726) and PEG linker length, ion mobility measurements show that shorter linkers constrain the ternary complex into more extended topologies, whereas longer, more flexible linkers allow dynamic sampling of relaxed, native-like conformations. SID directly probes noncovalent interfaces and shows that JQ1 complexes favor prompt PROTAC ejection, whereas tighter-binding I-BET726 complexes are more likely to retain the PROTAC at the interface. Complementing these kinetically-controlled gas-phase measurements, vT-ESI reveals a monophasic melting transition for a JQ1-mediated complex and a distinct biphasic melting profile for an I-BET726-mediated complex. The gas-phase activation measurements revealed targeting-ligand-driven differences in PROTAC ejection and retention, whereas vT-ESI uncovered distinct temperature-dependent disassembly pathways for the matched-linker-length JQ10L and IBET10L complexes. Together, these complementary techniques show how PROTAC architecture influences ternary-complex conformation, interfacial connectivity, and disassembly.",
  "abstract_shown": true,
  "affiliations": [
    "Georgia Institute of Technology"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "E. N. Whitford"
    },
    {
      "name": "J. D. Gilbert"
    },
    {
      "name": "M. M. Kostelic"
    },
    {
      "name": "M. A. Estrada"
    },
    {
      "name": "A. C. Ehlinger"
    },
    {
      "name": "T. A. Thibaudeau"
    },
    {
      "name": "S. M. McLoughlin"
    },
    {
      "affs": [
        0
      ],
      "name": "V. H. Wysocki"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/39fke1v33v958.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.29.755516",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755516v1.full",
  "id": "39fke1v33v958",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755516v1",
  "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",
      "biochemistry"
    ],
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7214931774",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755516v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/39fke1v33v958.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:28Z",
      "native_id": "10.64898/2026.09.29.755516",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755516v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Native Mass Spectrometry Reveals Distinct Effects of Linker Length and Targeting-Ligand Identity on PROTAC Ternary Complexes",
  "title_text": "Native Mass Spectrometry Reveals Distinct Effects of Linker Length and Targeting-Ligand Identity on PROTAC Ternary Complexes",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:28Z",
  "url": "https://research.draconitic.com/paper/39fke1v33v958",
  "venue": "bioRxiv",
  "versions": []
}