Structural basis for sirtuin 2 activity and modulation: Current state and opportunities

Sirtuin 2 (SIRT2) is a ubiquitously expressed cellular enzyme that deacylates protein lysine residues using NAD⁺ as a cofactor. SIRT2-mediated posttranslational modifications on a plethora of protein targets position the enzyme to exert a wide-ranging regulatory role in many physiological and pathological processes. More than 39 SIRT2 crystal structures in complex with substrates, products, mimetics of substrates and products, and modulators have been reported. The Rossmann fold of the catalytic core presents inducible acyl and cofactor-binding cavities that accommodate acyl chains of diverse lengths. These structures have provided information for the design of mechanism- and substrate-based inhibitors. Indeed, a specific SIRT2 selectivity pocket has been described and can be targeted by different chemotypes. Despite the determination of many crystal structures, numerous open questions remain, especially relating to the development of small molecule modulators, full or partial activation or inhibition, and relating these effects to different therapeutic applications. Additional questions include understanding the role of the disordered termini and the role of potential quaternary states (monomer, dimer, and trimer). Deeper insight into these issues may facilitate the development of SIRT2 selective modulators that can be tailored to different pathological scenarios, such as viral infections and cancers, in which either activation or inhibition of SIRT2 may be of therapeutic benefit. This review covers the following topics: (1) primary to quaternary and catalytic structural biology; (2) structural insights into molecular modulation of SIRT2 (inhibition and selectivity by mechanism-based inhibitors, substrate-mimicking inhibitors, C pocket-binding inhibitors, and selectivity pocket binding inhibitors, including insights to activation); and (3) the impact of structural variations (mutations, posttranslational modifications, polymorphs, protein interactions). Despite considerable progress, key knowledge gaps remain regarding the design of optimized SIRT2 modulators. Addressing these uncertainties, particularly within the realms of full/partial activation/inhibition, off-target effects, and tailoring modulators to specific pathologies, will require further investigation into the roles of the SIRT2-disordered termini, quaternary states, and posttranslational modifications. Ultimately, unraveling these intricacies holds the key to unlocking the therapeutic potential of SIRT2 modulation.