The Many (Inter)faces of Anti-CRISPRs: Modulation of CRISPR-Cas Structure and Dynamics by Mechanistically Diverse Inhibitors

The discovery of protein inhibitors of CRISPR-Cas systems, called anti-CRISPRs (Acrs), has enabled the development of highly controllable and precise CRISPR-Cas tools. Anti-CRISPRs share very little structural or sequential resemblance to each other or to other proteins, which raises intriguing questions regarding their modes of action. Many structure-function studies have shed light on the mechanism(s) of Acrs, which can act as orthosteric or allosteric inhibitors of CRISPR-Cas machinery, as well as enzymes that irreversibly modify CRISPR-Cas components. Only recently has the breadth of diversity of Acr structures and functions come to light, and this remains a rapidly evolving field. Here, we draw attention to a plethora of Acr mechanisms, with particular focus on how their action toward Cas proteins modulates conformation, dynamic (allosteric) signaling, nucleic acid binding, and cleavage ability.

Automated summary

The discovery of protein inhibitors of CRISPR-Cas systems, called anti-CRISPRs (Acrs), has revolutionized the field of CRISPR-Cas technology. These inhibitors have diverse structures and functions, and can act as orthosteric or allosteric inhibitors, as well as modify CRISPR-Cas components. Understanding the mechanisms of Acrs is crucial for the development of more precise and controllable CRISPR-Cas tools.