ArticleProceedings of the National Academy of Sciences of the United States of America2019
Allosteric modulation of a human protein kinase with monobodies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
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Who cites it
26 citing papers in PubMed, 52 citations in OpenAlex.
- Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Advances in pyrazolo[1,5-RSC advances · 2025Review
- CEP192 localises mitotic Aurora-A activity by priming its interaction with TPX2.The EMBO journal · 2024Article
- Special Issue: "Molecular Dynamics Simulations and Structural Analysis of Protein Domains".International journal of molecular sciences · 2024Article
- An Update on Protein Kinases as Therapeutic Targets-Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein-Protein Interactions.International journal of molecular sciences · 2023Review
- Conformation state-specific monobodies regulate the functions of flexible proteins through conformation trapping.Protein science : a publication of the Protein Society · 2023Article
- Article
- Allosteric regulation of kinase activity in living cells.bioRxiv : the preprint server for biology · 2023Article
- A biophysical framework for double-drugging kinases.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Structural basis for CEP192-mediated regulation of centrosomal AURKA.Science advances · 2023Article
- A biophysical framework for double-drugging kinases.bioRxiv : the preprint server for biology · 2023Article
- Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches.Journal of chemical information and modeling · 2023Review
- Probing conformational landscapes and mechanisms of allosteric communication in the functional states of the ABL kinase domain using multiscale simulations and network-based mutational profiling of allosteric residue potentials.The Journal of chemical physics · 2022Article
- Study of spatiotemporal regulation of kinase signaling using genetically encodable molecular tools.Current opinion in chemical biology · 2022Review
- Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Monobodies as tool biologics for accelerating target validation and druggable site discovery.RSC medicinal chemistry · 2021Review
- Chemical tools for dissecting cell division.Nature chemical biology · 2021Review
- Selective and noncovalent targeting of RAS mutants for inhibition and degradation.Nature communications · 2021Article
- Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis.Nature communications · 2021Article
- The high-energy transition state of the glutamate transporter homologue GltPh.The EMBO journal · 2021Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Despite being the subject of intense effort and scrutiny, kinases have proven to be consistently challenging targets in inhibitor drug design. A key obstacle has been promiscuity and consequent adverse effects of drugs targeting the ATP binding site. Here we introduce an approach to controlling kinase activity by using monobodies that bind to the highly specific regulatory allosteric pocket of the oncoprotein Aurora A (AurA) kinase, thereby offering the potential for more specific kinase modulators. Strikingly, we identify a series of highly specific monobodies acting either as strong kinase inhibitors or activators via differential recognition of structural motifs in the allosteric pocket. X-ray crystal structures comparing AurA bound to activating vs inhibiting monobodies reveal the atomistic mechanism underlying allosteric modulation. The results reveal 3 major advantages of targeting allosteric vs orthosteric sites: extreme selectivity, ability to inhibit as well as activate, and avoidance of competing with ATP that is present at high concentrations in the cells. We envision that exploiting allosteric networks for inhibition or activation will provide a general, powerful pathway toward rational drug design.
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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.