The xeroderma pigmentosum C (XPC) complex initiates nucleotide excision repair 
by recognizing DNA lesions before recruiting downstream factors. How XPC detects 
structurally diverse lesions embedded within normal DNA is unknown. Here we 
present a crystal structure that captures the yeast XPC orthologue (Rad4) on a 
single register of undamaged DNA. The structure shows that a disulphide-tethered 
Rad4 flips out normal nucleotides and adopts a conformation similar to that seen 
with damaged DNA. Contrary to many DNA repair enzymes that can directly reject 
non-target sites as structural misfits, our results suggest that Rad4/XPC uses a 
kinetic gating mechanism whereby lesion selectivity arises from the kinetic 
competition between DNA opening and the residence time of Rad4/XPC per site. 
This mechanism is further supported by measurements of Rad4-induced 
lesion-opening times using temperature-jump perturbation spectroscopy. Kinetic 
gating may be a general mechanism used by site-specific DNA-binding proteins to 
minimize time-consuming interrogations of non-target sites.