7M5W

Crystal structure of the HMG-C1 domain of human capicua bound to DNA

Summary for 7M5W

• Entry DOI: 10.2210/pdb7m5w/pdb
• Descriptor: Protein capicua homolog, DNA (5'-D(*GP*GP*TP*TP*AP*TP*GP*AP*AP*TP*GP*AP*AP*AP*AP*AP*GP*C)-3'), DNA (5'-D(*GP*CP*TP*TP*TP*TP*TP*CP*AP*TP*TP*CP*AP*TP*AP*AP*CP*C)-3'), ... (5 entities in total)
• Functional Keywords: helix-turn-helix, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 33031.48

Authors

Webb, J.P.,Liew, J.J.M.,Gnann, A.D.,Dowling, D.P. (deposition date: 2021-03-25, release date: 2022-04-06, Last modification date: 2025-11-05)

Primary citation

Webb, J.,Liew, J.J.M.,Gnann, A.D.,Ilkhani, K.,Patterson, M.,Paul, S.,Fores, M.,Jimenez, G.,Veraksa, A.,Dowling, D.P.
Molecular basis of DNA recognition by the HMG-box-C1 module of capicua.
Structure, 2025

PubMed Abstract: The HMG-box protein capicua (CIC) is a conserved transcriptional repressor with key functions in development and disease. CIC binding of DNA requires both its HMG-box and a separate domain called C1. How these domains cooperate to recognize specific DNA sequences is not known. Here, we report the crystal structure of the human CIC HMG-box and C1 domains complexed with a DNA oligomer containing a consensus octameric binding site. We find that both domains adopt tri-helical structures that pack against opposite sides of the DNA helix. The C1 domain folds into a helix-turn-helix (HTH) structure, inserting into the DNA major groove to enhance affinity. We investigate the system using molecular dynamics simulations and binding assays that interrogate the observed HMG-box and C1 domain interface and prominent cancer variants. Our results reveal a unique bipartite DNA-binding module and provide insights into the effects of cancer and domain interface mutations.

PubMed: 40967212
DOI: 10.1016/j.str.2025.08.018

Experimental method

X-RAY DIFFRACTION (2.95 Å)