Metalloallostery and Transition Metal Signaling: Bioinorganic Copper Chemistry Beyond Active Sites

Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal‐dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration. Metalloallostery, where metals regulate protein function through binding to a remote allosteric exosite rather than an active site, expands the roles of metals in biological chemistry. Using copper as a canonical example, we summarize advances in the field through imaging tools for labile metal pools, positive and negative allosteric transition metal signaling, and copper‐dependent regulation of cell proliferation and apoptosis.