️ Episode 236: XPD translocation and genetic disease etiology

In this episode of PaperCast Base by Base, we explore Computational modeling reveals how ATP-driven conformational cycles of the XPD helicase drive directional 5′→3′ translocation on single-stranded DNA and how mutations disrupt this process to cause disease

Study Highlights:
The authors combined molecular dynamics, partial nudged elastic band path optimization, transition path sampling, and Markov state modeling to map seven metastable on-path states that define XPD’s ATPase cycle. ATP binding and hydrolysis drive reciprocal rotations of the RecA2 and Arch domains, transmitted via a spring helix and spindle helix, that alternate DNA affinity at two defined constrictions at the 5′ and 3′ ends of the DNA-binding groove. Translocation proceeds in two phases: RecA2-driven sliding of ssDNA through Constriction 1 followed by ATP hydrolysis, constriction switching and sliding through Constriction 2, advancing one nucleotide per ATP. Mapping of missense mutations shows clustering of disease-associated residues at DNA- and ATP-binding sites and classifies mutations that impair DNA binding, ATPase function, or allosteric domain dynamics

Conclusion:
A detailed mechanistic map links XPD’s nucleotide-dependent conformational switching to directional ssDNA translocation and explains how perturbations of key residues underlie XP, CS, and TTD phenotypes

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Paul T, Yan C, Derdeyn-Blackwell G, Ivanov I. Translocation mechanism of xeroderma pigmentosum group D protein on single-stranded DNA and genetic disease etiology. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66834-1

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Keywords: XPD, DinG, ssDNA translocation, nucleotide excision repair, disease mutations