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Significance DNA replication and repair depend on AAA+ ATPase protein complexes called clamp loaders that open and load ring-shaped sliding clamps onto DNA. Using cryogenic electron microscopy, we determined the first structure of the human clamp loader (RFC), which is in an autoinhibited conformation while bound to the sliding clamp (PCNA). We assign this to be a reaction intermediate prior to clamp opening and propose a conformational change necessary for activation, leading to a unique paradigm for the AAA+ ATPase mechanism. We examined RFC’s interaction with a PCNA disease variant, which illuminates how this variant maintains tight interactions with some partners. Finally, mapping of cancer mutations onto RFC’s structure suggests stability as a key factor in proper function and human health.

Structure of the human clamp loader reveals an autoinhibited conformation of a substrate-bound AAA+ switch