6U81

Crystal Structure of the Double Homeodomain of DUX4 in Complex with a DNA aptamer

Summary for 6U81

• Entry DOI: 10.2210/pdb6u81/pdb
• Descriptor: Double homeobox protein 4, DNA (5'-D(*GP*CP*GP*TP*AP*AP*TP*CP*TP*AP*AP*TP*CP*AP*AP*CP*A)-3'), DNA (5'-D(*TP*GP*TP*TP*GP*AP*TP*TP*AP*GP*CP*CP*CP*AP*TP*TP*AP*CP*GP*C)-3'), ... (5 entities in total)
• Functional Keywords: dux tandem homeodomains, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 27033.31

Authors

Shi, K.,Aihara, H. (deposition date: 2019-09-04, release date: 2020-02-19, Last modification date: 2023-10-11)

Primary citation

Klingler, C.,Ashley, J.,Shi, K.,Stiefvater, A.,Kyba, M.,Sinnreich, M.,Aihara, H.,Kinter, J.
DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD.
Faseb J., 34:4573-4590, 2020

PubMed Abstract: Aberrant expression of the transcription factor double homeobox protein 4 (DUX4) can lead to a number of diseases including facio-scapulo-humeral muscular dystrophy (FSHD), acute lymphoblastic leukemia, and sarcomas. Inhibition of DUX4 may represent a therapeutic strategy for these diseases. By applying Systematic Evolution of Ligands by EXponential Enrichment (SELEX), we identified aptamers against DUX4 with specific secondary structural elements conveying high affinity to DUX4 as assessed by fluorescence resonance energy transfer and fluorescence polarization techniques. Sequences analysis of these aptamers revealed the presence of two consensus DUX4 motifs in a reverse complementary fashion forming hairpins interspersed with bulge loops at distinct positions that enlarged the binding surface with the DUX4 protein, as determined by crystal structure analysis. We demonstrate that insertion of specific structural elements into transcription factor binding oligonucleotides can enhance specificity and affinity.

PubMed: 32020675
DOI: 10.1096/fj.201902696

Experimental method

X-RAY DIFFRACTION (2.34 Å)