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Structural Characterization of Human Endonuclease III-like Protein 1 and Insights into Its Role in DNA Repair and Cancer
Ngo, Marcos
Ngo, Marcos
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Abstract
Human endonuclease III-like protein 1 (hNTHL1) is a base excision repair protein responsible for the removal of oxidized pyrimidines. Mutations in hNTHL1 are linked to colorectal and breast cancer, making structural characterization critical. This project aims to characterize the structure and conformational changes of hNTHL1 through X-ray crystallography and molecular dynamics (MD) simulations. Previously, this enzyme was solved in a non-catalytically competent or open conformation. This suggested that the protein must undergo significant interdomain rearrangement to position catalytic residues together for active site assembly (the closed conformation). This closed state of
hNTHL1 has only been achieved by substituting its interdomain linker with a shorter bacterial equivalent. Here, we report that a cancer-associated missense variant, V283E, adopts a closed conformation, and that co-crystallization experiments with the wild-type have captured a previously unobserved intermediate state. MD simulations initiated from each conformation reveal that hNTHL1 dynamically samples both conformers. These results establish that conformational interconversion is an intrinsic property of the enzyme and that cancer-associated mutations can shift the conformational equilibrium, leading to a reduction in catalytic activity.
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2027-05-04
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Department of Biochemistry