From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4 Article Swipe
Vera A. Spanke
,
Valentin J. Egger-Hoerschinger
,
Veronika Ruzsányi
,
Klaus R. Liedl
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1007/s10822-025-00589-1
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1007/s10822-025-00589-1
Cytochrome P450 3A4 (CYP3A4) is a membrane bound monooxygenase. It metabolizes the largest proportion of all orally ingested drugs. Ligands can enter and exit the enzyme through flexible tunnels, which co-determine CYP3A4’s ligand promiscuity. The flexibility can be represented by distinct conformational states of the enzyme. However, previous state definitions relied solely on crystal structures. We employed conventional molecular dynamics (cMD) simulations to sample the conformational space of CYP3A4. Five conformationally different crystal structures embedded in a membrane were simulated for 1 µs each. A Markov state model (MSM) coupled with spectral clustering (Robust Perron Cluster Analysis PCCA +) resulted in three distinct states: Two open conformations and an intermediate conformation. The tunnels inside CYP3A4 were calculated with CAVER3.0. Notably, we observed variations in bottleneck radii compared to those derived from crystallographic data. We want to point out the importance of simulations to characterize the dynamic behaviour. Moreover, we identified a mechanism, in which the membrane supports the opening of a tunnel. Therefore, CYP3A4 must be investigated in its membrane-bound state.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1007/s10822-025-00589-1
- https://link.springer.com/content/pdf/10.1007/s10822-025-00589-1.pdf
- OA Status
- hybrid
- Cited By
- 1
- References
- 78
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4408535875
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Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4408535875Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1007/s10822-025-00589-1Digital Object Identifier
- Title
-
From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4Work title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-03-17Full publication date if available
- Authors
-
Vera A. Spanke, Valentin J. Egger-Hoerschinger, Veronika Ruzsányi, Klaus R. LiedlList of authors in order
- Landing page
-
https://doi.org/10.1007/s10822-025-00589-1Publisher landing page
- PDF URL
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https://link.springer.com/content/pdf/10.1007/s10822-025-00589-1.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
hybridOpen access status per OpenAlex
- OA URL
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https://link.springer.com/content/pdf/10.1007/s10822-025-00589-1.pdfDirect OA link when available
- Concepts
-
Molecular dynamics, Chemistry, Membrane, CYP3A4, Ligand (biochemistry), Crystallography, Stereochemistry, Chemical physics, Cytochrome P450, Computational chemistry, Enzyme, Biochemistry, ReceptorTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
1Total citation count in OpenAlex
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2025: 1Per-year citation counts (last 5 years)
- References (count)
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78Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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