Merav Braitbard

Abstract Orthosteric inhibitors block enzyme active sites and prevent substrates from binding1. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on direct competition rather than selective recognition. Here we show that a molecular glue mechanism unexpectedly imparts substrate-dependent potency to CSN5i-3, an orthosteric inhibitor of the COP9 signalosome (CSN).

Highlights • One copy of CENP-N is lost for every two copies of CENP-C at mitotic onset • Structures of core centromeric nucleosome complex (CCNC) with 1 or 2 copies CENP-N • Natural centromere nucleosomal DNA conformation corresponds to robust CCNC assembly • Emerging model of mitotic centromeric chromatin with global and local asymmetries Summary Centromeric nucleosomes are at the interface of the chromosome and the kinetochore that connects to spindle microtubules in mitosis.