ArticleNature methods2025
Rational engineering of allosteric protein switches by in silico prediction of domain insertion sites.
Article in Nature methods, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Protein Surface Site Determines the Evolutionary Accessibility of Allosteric Regulation.bioRxiv : the preprint server for biology · 2026Article
- Design and optimization of a kinase-controlled allosteric switch.Nature methods · 2026Article
- Opportunities for artificial intelligence and synthetic biology in designing living drug delivery systems.Advanced drug delivery reviews · 2026Review
- AI-Predicted Model-Guided Rebuilding of the Experimental Structure of Mouse δ-Aminolevulinic Acid Dehydratase.International journal of molecular sciences · 2026Article
- Artificial intelligence in biologic drug discovery: A review of methodological evolution and therapeutic applications.Acta pharmaceutica Sinica. B · 2026Review
- Fusion Protein Technology to Enhance Pharmacological Properties of L-Asparaginases.Biomolecules · 2026Review
- Using Domain Insertion to Create Sulfite Reductases That Present Chemical-Dependent Activities.ACS synthetic biology · 2026Article
- Multimodal control of Cas13d activity through domain insertion at an allosteric hotspot.Nature communications · 2026Article
- Family-level specialization in protein domain insertion architectures.Protein science : a publication of the Protein Society · 2026Article
- Protein foundation models: a comprehensive survey.Science China. Life sciences · 2026Review
- Modular engineering of thermoresponsive allosteric proteins.Nature chemical biology · 2026Article
- Generative Protein Design: From Deep Learning Algorithms to Translational Applications.International journal of molecular sciences · 2026Review
- Phage-assisted evolution of allosteric protein switches.Nature communications · 2026Article
- Bioswitches: Towards programmable, on-demand control of therapeutic proteins.Clinical and translational medicine · 2026Article
- Engineering the Link: From Genome Interaction Maps to Functional Insight.Advanced biology · 2025Review
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Authors and funding
11 authors.
Funding
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Abstract
Domain insertion engineering is a powerful approach to juxtapose otherwise separate biological functions, resulting in proteins with new-to-nature activities. A prominent example are switchable protein variants, created by receptor domain insertion into effector proteins. Identifying suitable, allosteric sites for domain insertion, however, typically requires extensive screening and optimization. We present ProDomino, a machine learning pipeline to rationalize domain recombination, trained on a semisynthetic protein sequence dataset derived from naturally occurring intradomain insertion events. ProDomino robustly identifies domain insertion sites in proteins of biotechnological relevance, which we experimentally validated in Escherichia coli and human cells. Finally, we used light- and chemically regulated receptor domains as inserts and demonstrate the rapid, model-guided creation of potent, single-component opto- and chemogenetic protein switches. These include novel CRISPR-Cas9 and -Cas12a variants for inducible genome engineering in human cells. Our work enables one-shot domain insertion engineering and substantially accelerates the design of customized allosteric proteins.
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