ArticleBiochemistry2015
Two Loops Undergoing Concerted Dynamics Regulate the Activity of the ASH1L Histone Methyltransferase.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- Comprehensive multi-omics analysis of histone acetylation modulators identifies ASH1L as a novel aggressive marker for osteosarcoma.Discover oncology · 2025Article
- Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation.Nature communications · 2025Article
- Structure-Based Development of Novel Spiro-Piperidine ASH1L Inhibitors.Journal of medicinal chemistry · 2025Article
- Loss-of-function mutations of microRNA-142-3p promoteWorld journal of gastroenterology · 2025Article
- Novel heterozygousFrontiers in neurology · 2025Article
- Thioamides in medicinal chemistry and as small molecule therapeutic agents.European journal of medicinal chemistry · 2024Review
- Abnormal H3K4 enzyme catalytic activity and neuronal morphology caused by ASH1L mutations in individuals with Tourette syndrome.European child & adolescent psychiatry · 2024Article
- Autoinhibited Protein Database: a curated database of autoinhibitory domains and their autoinhibition mechanisms.Database : the journal of biological databases and curation · 2024Article
- Recent advances in developing degraders & inhibitors of lysine methyltransferases.Current opinion in chemical biology · 2023Review
- Exploring Methods of Targeting Histone Methyltransferases and Their Applications in Cancer Therapeutics.ACS chemical biology · 2022Review
- Structure, Activity, and Function of SETMAR Protein Lysine Methyltransferase.Life (Basel, Switzerland) · 2021Review
- A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain.Molecular psychiatry · 2021Article
- Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.Nature communications · 2021Article
- Covalent inhibition of NSD1 histone methyltransferase.Nature chemical biology · 2020Article
- Effect of H2A.Z deletion is rescued by compensatory mutations in Fusarium graminearum.PLoS genetics · 2020Article
- The molecular genetic make-up of male breast cancer.Endocrine-related cancer · 2019Article
- Human SETMAR is a DNA sequence-specific histone-methylase with a broad effect on the transcriptome.Nucleic acids research · 2019Article
- Article
- Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila.Nature communications · 2017Article
- H3K36 methyltransferases as cancer drug targets: rationale and perspectives for inhibitor development.Future medicinal chemistry · 2016Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
ASH1L (absent, small, or homeotic-like 1) is a histone methyltransferase (HMTase) involved in gene activation that is overexpressed in multiple forms of cancer. Previous studies of ASH1L's catalytic SET domain identified an autoinhibitory loop that blocks access of histone substrate to the enzyme active site. Here, we used both nuclear magnetic resonance and X-ray crystallography to identify conformational dynamics in the ASH1L autoinhibitory loop. Using site-directed mutagenesis, we found that point mutations in the autoinhibitory loop that perturb the structure of the SET domain result in decreased enzyme activity, indicating that the autoinhibitory loop is not a simple gate to the active site but is rather a key feature critical to ASH1L function. We also identified a second loop in the SET-I subdomain of ASH1L that experiences conformational dynamics, and we trapped two different conformations of this loop using crystallographic studies. Mutation of the SET-I loop led to a large decrease in ASH1L enzymatic activity in addition to a significant conformational change in the SET-I loop, demonstrating the importance of the structure and dynamics of the SET-I loop to ASH1L function. Furthermore, we found that three C-terminal chromatin-interacting domains greatly enhance ASH1L enzymatic activity and that ASH1L requires native nucleosome substrate for robust activity. Our study illuminates the role of concerted conformational dynamics in ASH1L function and identifies structural features important for ASH1L enzymatic activity.
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