{
  "abstract": "Cytochrome P450 3A4 (CYP3A4) metabolizes roughly half of all marketed drugs, and its inhibition can cause clinically significant drug-drug interactions. The enzyme accommodates chemically diverse ligands, making binding modes and metabolic outcomes difficult to predict. Previous X-ray crystallography efforts have leveraged a truncated construct without the N-terminal segment that tethers CYP3A4 to the membrane. Here we show that the same construct assembles into a symmetric trimer that can be resolved by cryo-EM and determine structures of both unliganded and ligand-bound CYP3A4. Multiple ligands are resolved with density consistent with several mutually exclusive conformations. Protein remodeling to reshape the binding pocket is concentrated in the F/G loop, which is poorly resolved and unmodeled in many X-ray structures. These features likely underlie the poor predictive performance of co-folding methods on this target. The routine use of cryo-EM to resolve CYP3A4 ligand-bound complexes will provide the ground truth data needed to make predictive models of drug metabolism useful in practice.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "A. K. Orta"
    },
    {
      "name": "J.-H. Schäfer"
    },
    {
      "name": "G. J. Correy"
    },
    {
      "name": "J. O. Norman"
    },
    {
      "name": "J. Pampel"
    },
    {
      "name": "K. K. Huddleston"
    },
    {
      "name": "H. MacDermott-Opeskin"
    },
    {
      "name": "E. B. Miller"
    },
    {
      "name": "G. Reggiano"
    },
    {
      "name": "J. P. Rodrigues"
    },
    {
      "name": "G. C. Lander"
    },
    {
      "name": "W. P. Walters"
    },
    {
      "affs": [
        0
      ],
      "name": "J. S. Fraser"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8pye01k685pyr.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.01.748687",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748687v1.full",
  "id": "8pye01k685pyr",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748687v1",
  "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",
      "biophysics"
    ],
    [
      "openalex",
      "3004|Pharmacogenetics and Drug Metabolism"
    ]
  ],
  "openalex": "W7207849693",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748687v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8pye01k685pyr.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:37Z",
      "native_id": "10.64898/2026.09.01.748687",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748687v5"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM",
  "title_text": "Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:28Z",
  "url": "https://research.draconitic.com/paper/8pye01k685pyr",
  "venue": "bioRxiv",
  "versions": []
}