ArticleThe Journal of biological chemistry2019
The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region.
Article in The Journal of biological chemistry, 2019. 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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17 citing papers in PubMed, 32 citations in OpenAlex.
- Synthesis of Novel Acetylene-Containing Phosphonates, Their Antiviral Activity, and Their Cytotoxicity to Different Cancer Cell Lines.Molecules (Basel, Switzerland) · 2026Article
- In-vitro and In-silico Evaluation of Supercritical Extract of Acacia Auriculiformis against Breast Cancer.Cell biochemistry and biophysics · 2026Article
- Comparative Efficacy of CK2 Inhibitors CX-4945 and SGC-CK2-2 on CK2 Signaling.International journal of molecular sciences · 2025Article
- An atlas of bacterial serine-threonine kinases reveals functional diversity and key distinctions from eukaryotic kinases.Science signaling · 2025Article
- Virtual Screening, Molecular Dynamics, and Mechanism Study of Homeodomain-Interacting Protein Kinase 2 Inhibitor in Renal Fibroblasts.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Genome-wide epistasis analysis reveals gene-gene interaction network on an intermediate endophenotype P-tau/AβScientific reports · 2024Article
- Computational analysis of regulatory regions in human protein kinases.Protein science : a publication of the Protein Society · 2023Article
- Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders.FEBS letters · 2023Review
- HIPK2 in the physiology of nervous system and its implications in neurological disorders.Biochimica et biophysica acta. Molecular cell research · 2023Review
- Silmitasertib (CX-4945), a Clinically Used CK2-Kinase Inhibitor with Additional Effects on GSK3β and DYRK1A Kinases: A Structural Perspective.Journal of medicinal chemistry · 2023Article
- Targeting pre-mRNA splicing in cancers: roles, inhibitors, and therapeutic opportunities.Frontiers in oncology · 2023Review
- Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation.Nature communications · 2021Article
- Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
- A novel isoform of Homeodomain-interacting protein kinase-2 promotes YAP/TEAD transcriptional activity in NSCLC cells.Oncotarget · 2021Article
- Emerging roles of the αC-β4 loop in protein kinase structure, function, evolution, and disease.IUBMB life · 2020Review
- Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes.The Journal of biological chemistry · 2020Article
- The long-awaited structure of HIPK2.The Journal of biological chemistry · 2019Article
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9 authors at 2 institutions in 1 country.
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Abstract
The homeodomain-interacting protein kinase (HIPK) family is comprised of four nuclear protein kinases, HIPK1-4. HIPK proteins phosphorylate a diverse range of transcription factors involved in cell proliferation, differentiation, and apoptosis. HIPK2, thus far the best-characterized member of this largely understudied family of protein kinases, plays a role in the activation of p53 in response to DNA damage. Despite this tumor-suppressor function, HIPK2 is also found overexpressed in several cancers, and its hyperactivation causes chronic fibrosis. There are currently no structures of HIPK2 or of any other HIPK kinase. Here, we report the crystal structure of HIPK2's kinase domain bound to CX-4945, a casein kinase 2α (CK2α) inhibitor currently in clinical trials against several cancers. The structure, determined at 2.2 Å resolution, revealed that CX-4945 engages the HIPK2 active site in a hybrid binding mode between that seen in structures of CK2α and Pim1 kinases. The HIPK2 kinase domain crystallized in the active conformation, which was stabilized by phosphorylation of the activation loop. We noted that the overall kinase domain fold of HIPK2 closely resembles that of evolutionarily related dual-specificity tyrosine-regulated kinases (DYRKs). Most significant structural differences between HIPK2 and DYRKs included an absence of the regulatory N-terminal domain and a unique conformation of the CMGC-insert region and of a newly defined insert segment in the αC-β4 loop. This first crystal structure of HIPK2 paves the way for characterizing the understudied members of the HIPK family and for developing HIPK2-directed therapies for managing cancer and fibrosis.
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