ALC1 Finds a New Foothold on the Nucleosome’s Super-Groove

Nucleosomes act as recognition platforms for chromatin-binding factors that coordinate genome maintenance. A distinct structural feature of the nucleosome is the alignment of the DNA major and minor grooves across both gyres, forming continuous major and minor super-grooves. Despite this prominent feature, only one example of a naturally occurring protein binding to a super-groove is documented at the structural level to date. The chromatin remodeler Amplified in Liver Cancer 1 (ALC1) is a key component of the DNA damage response and a promising therapeutic target in cancer. Through extensive classification of our cryo-electron microscopy data, we identified a previously unresolved ALC1-nucleosome complex characterized by a loosely bound conformation of ALC1. This conformation represents an intermediate between the auto-inhibited and active states, and provides new structural insights into the conformational transitions that regulate ALC1 activity. In this intermediate state, the linker of ALC1 engages the nucleosome’s minor DNA super-groove across both gyres in a recognition mode observed for the first time in a naturally occurring protein.