8T0F

Crystal structure of the PEG10 promoter-bound ONECUT2 DNA-binding domain

Summary for 8T0F

• Entry DOI: 10.2210/pdb8t0f/pdb
• Descriptor: One cut domain family member 2, DNA (5'-D(P*AP*GP*AP*TP*CP*GP*AP*TP*TP*TP*GP*C)-3'), DNA (5'-D(P*GP*CP*AP*AP*AP*TP*CP*GP*AP*TP*CP*T)-3'), ... (4 entities in total)
• Functional Keywords: onecut family transcription factor cut-homeodomain prostate cancer dna-binding, transcription, transcription-dna complex, transcription/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 26017.53

Authors

Chatterjee, A.,Katiki, M.,Murali, R. (deposition date: 2023-05-31, release date: 2024-08-28, Last modification date: 2024-11-27)

Primary citation

Chatterjee, A.,Gallent, B.,Katiki, M.,Qian, C.,Harter, M.R.,Silletti, S.,Komives, E.A.,Freeman, M.R.,Murali, R.
The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2.
Nat Commun, 15:9037-9037, 2024

PubMed Abstract: The CUT and homeodomain are ubiquitous DNA binding elements often tandemly arranged in multiple transcription factor families. However, how the CUT and homeodomain work concertedly to bind DNA remains unknown. Using ONECUT2, a driver and therapeutic target of advanced prostate cancer, we show that while the CUT initiates DNA binding, the homeodomain thermodynamically stabilizes the ONECUT2-DNA complex through allosteric modulation of CUT. We identify an arginine pair in the ONECUT family homeodomain that can adapt to DNA sequence variations. Base interactions by this ONECUT family-specific arginine pair as well as the evolutionarily conserved residues are critical for optimal DNA binding and ONECUT2 transcriptional activity in a prostate cancer model. The evolutionarily conserved base interactions additionally determine the ONECUT2-DNA binding energetics. These findings provide insights into the cooperative DNA binding by CUT-homeodomain proteins.

PubMed: 39426953
DOI: 10.1038/s41467-024-53159-8

Experimental method

X-RAY DIFFRACTION (2.61 Å)