9WA7

Crystal Structure of Human NFIX in Complex with TGGCA(N3)TGCCA Palindromic DNA

Summary for 9WA7

• Entry DOI: 10.2210/pdb9wa7/pdb
• Descriptor: Nuclear factor 1 X-type, DNA (5'-D(*AP*GP*TP*TP*GP*GP*CP*AP*AP*GP*AP*TP*GP*CP*CP*AP*TP*C)-3'), DNA (5'-D(*GP*AP*TP*GP*GP*CP*AP*TP*CP*TP*TP*GP*CP*CP*AP*AP*CP*T)-3'), ... (5 entities in total)
• Functional Keywords: nfix, transcription factor, skeletal muscle development, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 30284.19

Authors

Zhu, C.,Chen, X.,Qin, C.,Song, H. (deposition date: 2025-08-11, release date: 2026-03-11)

Primary citation

Zhu, C.,Liu, S.,Chen, X.,Qin, C.,Wang, Y.,Xue, C.,Li, L.,Du, W.,Chen, X.,Li, X.,Shen, J.,Song, H.
Mechanistic Insights Into NFIX-Mediated DNA Recognition and Transcriptional Regulation in Skeletal Muscle.
Smart Med, 5:e70027-e70027, 2026

PubMed Abstract: Skeletal muscle is essential for voluntary movement and exhibits a remarkable capacity for regeneration following injury. NFIX, a member of the Nuclear Factor I (NFI) family of transcription factors, plays a critical role in both skeletal muscle development and regeneration. Despite its emerging importance, the molecular basis of NFIX-mediated DNA recognition and transcriptional regulation in skeletal muscle remains poorly defined. Here, we demonstrate that NFIX promotes key cellular processes in skeletal muscle cells, as siRNA-mediated knockdown of NFIX significantly reduces cell proliferation, increases apoptosis, and impairs differentiation. Transcriptomic analysis revealed that NFIX regulates a network of genes involved in muscle metabolism, stress responses, and immune inflammatory responses. Biophysical characterization showed that NFIX exists as a monomer in solution and binds palindromic DNA with a 1:1 stoichiometry. A high-resolution crystal structure of the NFIX bound to palindromic DNA reveals a monomeric binding mode driven by base-specific recognition of the TGGCA motif. Mutations that disrupt key DNA-contacting residues abolished both DNA binding and transcriptional activation in luciferase reporter assays. Together, these findings define the molecular mechanism of NFIX-dependent gene regulation in skeletal muscle and establish a structural framework for its function, providing new insights into the potential therapeutic targeting of NFIX in muscle diseases.

PubMed: 41623611
DOI: 10.1002/smmd.70027

Experimental method

X-RAY DIFFRACTION (2.31 Å)