ArticleProceedings of the National Academy of Sciences of the United States of America2012
LSD1/CoREST is an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 64 citations in OpenAlex.
- Systematic Review and Meta-Analysis of Lysine-Specific Demethylase 1 Expression as a Prognostic Biomarker of Cancer Survival and Disease Progression.Cancer control : journal of the Moffitt Cancer CenterPooled it
- Histone modification cross-talk: analytical tools and molecular mechanisms.The Biochemical journal · 2026Review
- Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1.Nature chemical biology · 2025Article
- A NR2E1-interacting peptide of LSD1 inhibits the proliferation of brain tumour initiating cells.Cell proliferation · 2023Article
- LSD1 for the Targeted Regulation of Adipose Tissue.Current issues in molecular biology · 2022Review
- Structural Insight of KSIII (β-Ketoacyl-ACP Synthase)-like Acyltransferase ChlB3 in the Biosynthesis of Chlorothricin.Molecules (Basel, Switzerland) · 2022Article
- Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy.The Journal of clinical investigation · 2021Article
- Crystal Structure of the LSD1/CoREST Histone Demethylase Bound to Its Nucleosome Substrate.Molecular cell · 2020Article
- Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex.Cell reports · 2020Article
- Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A.Nutrients · 2019Article
- Pharmacological Inhibition of LSD1 for Cancer Treatment.Molecules (Basel, Switzerland) · 2018Review
- Order-disorder transition of intrinsically disordered kinase inducible transactivation domain of CREB.The Journal of chemical physics · 2018Article
- LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Synergistic regulation mechanism of iperoxo and LY2119620 for muscarinic acetylcholine M2 receptor.RSC advances · 2018Article
- Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia.Cell reports · 2018Article
- Lysine-Specific Demethylase 1A as a Promising Target in Acute Myeloid Leukemia.Frontiers in oncology · 2018Review
- Identification of downstream metastasis-associated target genes regulated by LSD1 in colon cancer cells.Oncotarget · 2017Article
- LSD1 Substrate Binding and Gene Expression Are Affected by HDAC1-Mediated Deacetylation.ACS chemical biology · 2017Article
- Conformation Dynamics of the Intrinsically Disordered Protein c-Myb with theRSC advances · 2017Article
- Dynamics Correlation Network for Allosteric Switching of PreQ1 Riboswitch.Scientific reports · 2016Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The complex of lysine-specific demethylase-1 (LSD1/KDM1A) with its corepressor protein CoREST is an exceptionally relevant target for epigenetic drugs. Here, we provide insight into the local and global changes of LSD1/CoREST conformational dynamics that occur upon H3 binding on the basis of a total cumulative time of one microsecond molecular dynamics simulation. The LSD1/CoREST complex functions as an allosteric nanoscale-binding clamp, which is regulated by substrate binding. In the unbound state, LSD1/CoREST reversibly visits clamp states that are more open or significantly more closed compared with the available X-ray crystal structures. The Lys triad of residues Lys355, Lys357, and Lys359 gates the entrance of the H3 pocket. H3 binding shifts the pocket breathing dynamics toward open, higher-volume states while reducing the overall flexibility of the LSD1/CoREST nanoscale clamp. We show that the H3 pocket is an allosteric site for the regulation of the rotation of the amino oxidase domain with respect to the Tower domain. The allosteric mechanism relies on the specific reduction of nanoscale domain rotation upon local H3-tail binding. Instead, clamp opening/closing motions that do not involve domain rotation only reduce in amplitude yet are dominant in the bound state. Overall, our data suggest that the H3 binding pocket is a central target site to (i) switch off LSD1 amino oxidase activity, thus H3-tail demethylation; (ii) block the competitive binding of transcription factors; and (iii) prevent chromatin anchoring to LSD1/CoREST. This study underscores the importance of receptor flexibility for future epigenetic drug discovery.
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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.