Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology.

ABSTRACT: XPD is a key nucleotide excision repair (NER) protein whose function is vital for genome integrity. During NER, XPD serves as a 5'-3' single-strand DNA translocase that enables lesion scanning and verification in genomic DNA. Yet, its translocation mechanism is incompletely understood. Here we use molecular simulations and chain-of-replicas path optimization methods to model the ATP-driven translocation mechanisms of XPD and its bacterial homolog DinG, revealing all on-path metastable intermediates and corresponding kinetic rates. We identify the XPD(DinG) global domain motions that modulate the strength of DNA association at the opposing ends of the DNA-binding groove. During the ATP hydrolysis cycle, alternating weak and strong interactions at two defined groove constrictions enable DNA

SUBMITTER: Paul T 

PROVIDER: S-EPMC12753804 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature