ArticlePloS one2011
Co-crystal structures of inhibitors with MRCKβ, a key regulator of tumor cell invasion.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- Modeling patient variants of Cnot1 and Cdc42bpb results in distinct forms of congenital diaphragmatic hernia in mice.Human molecular genetics · 2026Article
- Modeling patient variants ofbioRxiv : the preprint server for biology · 2026Article
- MRCKα represses GEF-H1 mediated RhoA activation to promote ovarian cancer spheroid growth and invasion.bioRxiv : the preprint server for biology · 2026Article
- RHOA at the intersection of inflammation-driven and sporadic colorectal cancer.Frontiers in immunology · 2026Review
- Genetic Alterations in Atypical Cerebral Palsy Identified Through Chromosomal Microarray and Exome Sequencing.International journal of molecular sciences · 2025Article
- KD025 Is a Casein Kinase 2 Inhibitor That Protects Against Glucolipotoxicity in β-Cells.Diabetes · 2024Article
- Characterization of Anticancer Effects of the Analogs of DJ4, a Novel Selective Inhibitor of ROCK and MRCK Kinases.Pharmaceuticals (Basel, Switzerland) · 2023Article
- A critical evaluation of protein kinase regulation by activation loop autophosphorylation.eLife · 2023Article
- Review
- Label-Free Quantitative Proteomics to Explore the Action Mechanism of the Pharmaceutical-GradeMolecules (Basel, Switzerland) · 2022Article
- Article
- MRCK: a master regulator of tissue remodeling or another 'ROCK' in the epithelial block?Tissue barriers · 2021Review
- Article
- Article
- The CDC42 effector protein MRCKβ autophosphorylates on Threonine 1108.Small GTPases · 2020Article
- Targeting Rho GTPase Signaling Networks in Cancer.Frontiers in cell and developmental biology · 2020Review
- Article
- Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer.Cancer research · 2018Article
- PAK4 crystal structures suggest unusual kinase conformational movements.Biochimica et biophysica acta. Proteins and proteomics · 2018Article
- Made to measure - keeping Rho kinase at a distance.Small GTPases · 2016Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
MRCKα and MRCKβ (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKα and MRCKβ influence cell shape and motility. We report further evidence for MRCKα and MRCKβ contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKα and MRCKβ together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKβ kinase assay and found 11 compounds that inhibited enzyme activity >80% at 3 µM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC(50) values for MRCKα and MRCKβ. We also describe the crystal structure of MRCKβ in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned αC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts.
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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.