ArticleeLife2021
Enhanced specificity mutations perturb allosteric signaling in CRISPR-Cas9.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- Molecular mechanisms and biotechnology applications of CRISPR-Cas12a.Nature reviews. Molecular cell biology · 2026Review
- Mapping Allosteric Communication in the Nucleosome with Conditional Activity.Journal of chemical information and modeling · 2026Article
- A Computational Model for Nme1Cas9 HNH Activation Driven by Dynamic Interface Engineering at Residues S593 and W596.Biomolecules · 2026Article
- Computation and deep-learning-driven advances in CRISPR genome editing.Nature structural & molecular biology · 2026Review
- Therapeutic in vivo genome editing: innovations and challenges in rAAV vector-based CRISPR delivery.Gene therapy · 2026Review
- Mapping Allosteric Communication in the Nucleosome with Conditional Activity.bioRxiv : the preprint server for biology · 2025Article
- Design Rules for Expanding PAM Compatibility in CRISPR-Cas9 from the VQR, VRER and EQR variants.bioRxiv : the preprint server for biology · 2025Article
- Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2.Protein science : a publication of the Protein Society · 2025Article
- A Cryptic Binding Pocket Regulates the Metal-Dependent Activity of Cas9.bioRxiv : the preprint server for biology · 2025Article
- Prime editor with rational design and AI-driven optimization for reverse editing window and enhanced fidelity.Nature communications · 2025Article
- Article
- Unveiling Cas8 dynamics and regulation within a transposon-encoded Cascade-TniQ complex.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dynamic sampling of a surveillance state enables DNA proofreading by Cas9.Cell chemical biology · 2025Article
- Article
- Exploring CRISPR-Cas9 HNH-Domain-Catalyzed DNA Cleavage Using Accelerated Quantum Mechanical Molecular Mechanical Free Energy Simulation.Biochemistry · 2025Article
- Flexibility in PAM Recognition Expands DNA Targeting in xCas9.bioRxiv : the preprint server for biology · 2025Article
- Graph theory approaches for molecular dynamics simulations.Quarterly reviews of biophysics · 2024Article
- Probing Electrostatic Interactions in DNA-Bound CRISPR/Cas9 Complexes by Molecular Dynamics Simulations.ACS omega · 2024Article
- A parameterized two-domain thermodynamic model explains diverse mutational effects on protein allostery.eLife · 2024Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
CRISPR-Cas9 (clustered regularly interspaced short palindromic repeat and associated Cas9 protein) is a molecular tool with transformative genome editing capabilities. At the molecular level, an intricate allosteric signaling is critical for DNA cleavage, but its role in the specificity enhancement of the Cas9 endonuclease is poorly understood. Here, multi-microsecond molecular dynamics is combined with solution NMR and graph theory-derived models to probe the allosteric role of key specificity-enhancing mutations. We show that mutations responsible for increasing the specificity of Cas9 alter the allosteric structure of the catalytic HNH domain, impacting the signal transmission from the DNA recognition region to the catalytic sites for cleavage. Specifically, the K855A mutation strongly disrupts the allosteric connectivity of the HNH domain, exerting the highest perturbation on the signaling transfer, while K810A and K848A result in more moderate effects on the allosteric communication. This differential perturbation of the allosteric signal correlates to the order of specificity enhancement (K855A > K848A ~ K810A) observed in biochemical studies, with the mutation achieving the highest specificity most strongly perturbing the signaling transfer. These findings suggest that alterations of the allosteric communication from DNA recognition to cleavage are critical to increasing the specificity of Cas9 and that allosteric hotspots can be targeted through mutational studies for improving the system's function.
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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.