9BS2

Glycosylase MutY variant R149Q in complex with DNA containing d(8-oxo-G) paired with a product analog (THF) to 1.51 A resolution

Summary for 9BS2

• Entry DOI: 10.2210/pdb9bs2/pdb
• Related: 8FAY
• Descriptor: Adenine DNA glycosylase, DNA (5'-D(*AP*AP*GP*AP*CP*(8OG)P*TP*GP*GP*AP*C)-3'), DNA (5'-D(*TP*GP*TP*CP*CP*AP*(3DR)P*GP*TP*CP*T)-3'), ... (7 entities in total)
• Functional Keywords: protein-dna complex, dna repair, base excision repair, hydrolase, hydrolase-dna complex, hydrolase/dna
• Biological source: Geobacillus stearothermophilus; More
• Total number of polymer chains: 3
• Total formula weight: 49210.08

Authors

Trasvina-Arenas, C.H.,Tamayo, N.,Lin, W.J.,Demir, M.,Fisher, A.J.,David, S.S.,Horvath, M.P. (deposition date: 2024-05-12, release date: 2024-10-30, Last modification date: 2025-04-30)

Primary citation

Trasvina-Arenas, C.H.,Dissanayake, U.C.,Tamayo, N.,Hashemian, M.,Lin, W.J.,Demir, M.,Hoyos-Gonzalez, N.,Fisher, A.J.,Cisneros, G.A.,Horvath, M.P.,David, S.S.
Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair.
Nat Commun, 16:3596-3596, 2025

PubMed Abstract: MUTYH is a clinically important DNA glycosylase that thwarts mutations by initiating base-excision repair at 8-oxoguanine (OG):A lesions. The roles for its [4Fe-4S] cofactor in DNA repair remain enigmatic. Functional profiling of cancer-associated variants near the [4Fe-4S] cofactor reveals that most variations abrogate both retention of the cofactor and enzyme activity. Surprisingly, R241Q and N238S retained the metal cluster and bound substrate DNA tightly, but were completely inactive. We determine the crystal structure of human MUTYH bound to a transition state mimic and this shows that Arg241 and Asn238 build an H-bond network connecting the [4Fe-4S] cluster to the catalytic Asp236 that mediates base excision. The structure of the bacterial MutY variant R149Q, along with molecular dynamics simulations of the human enzyme, support a model in which the cofactor functions to position and activate the catalytic Asp. These results suggest that allosteric cross-talk between the DNA binding [4Fe-4S] cofactor and the base excision site of MUTYH regulate its DNA repair function.

PubMed: 40234396
DOI: 10.1038/s41467-025-58361-w

Experimental method

X-RAY DIFFRACTION (1.51 Å)