9WOY

Crystal Structure of the MLH1 Protein Bound to the FAN1 Peptide

Summary for 9WOY

• Entry DOI: 10.2210/pdb9woy/pdb
• Descriptor: DNA mismatch repair protein Mlh1, Fanconi-associated nuclease 1 (3 entities in total)
• Functional Keywords: protein-peptide complex, dna damage repair, huntington's disease, trinucleotide repeat instability, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 63042.04

Authors

Chen, Y.C.,Liu, Y.L.,Shang, X.C. (deposition date: 2025-09-07, release date: 2026-08-12)

Primary citation

Chen, Y.,Hu, H.,Shang, X.,Fishwick, K.M.,Greco, G.,Xiao, Q.,Zhou, Y.,Huang, Q.,Jiang, T.,Huang, X.,Wang, G.,Zhen, X.,Xu, G.,Qin, S.,Sartori, A.A.,Liu, Y.
Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.
Nat Commun, 2026

PubMed Abstract: Huntington's disease is driven by CAG repeat expansion in the mutant huntingtin gene. Nuclease FAN1 and mismatch repair protein MLH1 regulate repeat expansion through direct interaction, but the underlying structural basis remains unclear. Here, we show that the MLH1 C-terminal domain binds to FAN1-derived peptides containing either the MIP or MIM motif with comparable affinities. Crystal structures of this domain bound to each motif provide structural insights into human MLH1-FAN1 interaction, revealing a conserved mechanism for FAN1-MIP recognition and a previously unrecognized binding site on MLH1, termed the S3 site, for FAN1-MIM engagement. Co-immunoprecipitation assays confirmed that mutation of key MLH1 residues disrupts FAN1 binding in cells. These findings establish the molecular basis of MLH1-FAN1 recognition and provide a structural framework for understanding the regulation of CAG repeat expansion in Huntington's disease.

PubMed: 42409804
DOI: 10.1038/s41467-026-74991-0

Experimental method

X-RAY DIFFRACTION (2.28 Å)