ArticleNature chemistry2016
Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24.
Article in Nature chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 63 citations in OpenAlex.
- Effects of Ritonavir, Lopinavir, and Alcohol on ABC Transporters and Secretion of Bile Acid and Bilirubin in Senescent Hepatocytes.International journal of molecular sciences · 2026Article
- AIDS patients suffer higher risk of advanced knee osteoarthritis progression due to lopinavir-induced Zmpste24 inhibition.Bone research · 2025Article
- Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.International journal of molecular sciences · 2023Review
- A Liquid Chromatography-Mass Spectrometry Method to Study the Interaction between Membrane Proteins and Low-Molecular-Weight Compound Mixtures.Molecules (Basel, Switzerland) · 2022Article
- High-Resolution Native Mass Spectrometry.Chemical reviews · 2022Review
- Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.Aging cell · 2022Article
- MetFish: a Metabolomics Pipeline for Studying Microbial Communities in Chemically Extreme Environments.mSystems · 2021Article
- Sensing mechanisms of iron-sulfur cluster regulatory proteins elucidated using native mass spectrometry.Dalton transactions (Cambridge, England : 2003) · 2021Article
- Native Mass Spectrometry of Iron-Sulfur Proteins.Methods in molecular biology (Clifton, N.J.) · 2021Article
- A Pan-Cancer Analysis of Transcriptome and Survival Reveals Prognostic Differentially Expressed LncRNAs and Predicts Novel Drugs for Glioblastoma Multiforme Therapy.Frontiers in genetics · 2021Article
- The mitochondrial ADP/ATP carrier exists and functions as a monomer.Biochemical Society transactions · 2020Review
- Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology.Journal of molecular biology · 2020Review
- Assembly and regulation of the chlorhexidine-specific efflux pump AceI.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury.Hepatology communications · 2020Article
- The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24.Proteins · 2020Article
- Deficiency in ZMPSTE24 and resulting farnesyl-prelamin A accumulation only modestly affect mouse adipose tissue stores.Journal of lipid research · 2020Article
- Studying biomolecular folding and binding using temperature-jump mass spectrometry.Nature communications · 2020Article
- Defining substrate requirements for cleavage of farnesylated prelamin A by the integral membrane zinc metalloprotease ZMPSTE24.PloS one · 2020Article
- Interrogating Membrane Protein Structure and Lipid Interactions by Native Mass Spectrometry.Methods in molecular biology (Clifton, N.J.) · 2020Article
- Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies.JCI insight · 2019Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or non-specific binding to unintended membrane protein targets. However, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here, we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A. We monitored the proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found retention of the C-terminal peptide product with the enzyme. We also resolved binding of zinc, lipids and HIV protease inhibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to ZMPSTE24. Our results not only have relevance for the progeria-like side effects of certain HIV protease inhibitor drugs, but also highlight new approaches for documenting off-target drug binding.
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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.