ArticleCell chemical biology2018
Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase.
Article in Cell chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 31 citations in OpenAlex.
- Novel noscapine derivative induces AML differentiation by dual-engaging DHODH and mitochondrial lipids to trigger a metabolic-epigenetic-transcriptional cascade.Acta pharmaceutica Sinica. B · 2026Article
- Machine learning-assisted screening of natural product database for the identification of novel chalcone-based derivative as a potent DHODH inhibitor in cancer therapy.Discover oncology · 2026Article
- A Hit Prioritization Strategy for Compound Library Screening Using LiP-MS and Molecular Dynamics Simulations Applied to KRas G12D Inhibitors.Analytical chemistry · 2025Article
- The application of nanodiscs in membrane protein drug discovery & development and drug delivery.Frontiers in chemistry · 2024Review
- Advances in mass spectrometry to unravel the structure and function of protein condensates.Nature protocols · 2023Review
- Complementing machine learning-based structure predictions with native mass spectrometry.Protein science : a publication of the Protein Society · 2022Article
- Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?Bioscience reports · 2022Article
- Exploring Thermal Sensitivities and Adaptations of Oxidative Phosphorylation Pathways.Metabolites · 2022Review
- Structural insights into inhibition of the drug target dihydroorotate dehydrogenase by bacterial hydroxyalkylquinolines.RSC chemical biology · 2022Article
- Predicting protein-membrane interfaces of peripheral membrane proteins using ensemble machine learning.Briefings in bioinformatics · 2022Article
- New Insights into the Interaction of Class II Dihydroorotate Dehydrogenases with Ubiquinone in Lipid Bilayers as a Function of Lipid Composition.International journal of molecular sciences · 2022Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- The Profound Influence of Lipid Composition on the Catalysis of the Drug Target NADH Type II Oxidoreductase.Membranes · 2021Article
- DHODH and cancer: promising prospects to be explored.Cancer & metabolism · 2021Review
- Review
- Scratching the surface: native mass spectrometry of peripheral membrane protein complexes.Biochemical Society transactions · 2020Review
- Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties.Molecular cancer therapeutics · 2019Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The interactions between proteins and biological membranes are important for drug development, but remain notoriously refractory to structural investigation. We combine non-denaturing mass spectrometry (MS) with molecular dynamics (MD) simulations to unravel the connections among co-factor, lipid, and inhibitor binding in the peripheral membrane protein dihydroorotate dehydrogenase (DHODH), a key anticancer target. Interrogation of intact DHODH complexes by MS reveals that phospholipids bind via their charged head groups at a limited number of sites, while binding of the inhibitor brequinar involves simultaneous association with detergent molecules. MD simulations show that lipids support flexible segments in the membrane-binding domain and position the inhibitor and electron acceptor-binding site away from the membrane surface, similar to the electron acceptor-binding site in respiratory chain complex I. By complementing MS with MD simulations, we demonstrate how a peripheral membrane protein uses lipids to modulate its structure in a similar manner as integral membrane proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.