6u82

Crystal Structure of the Double Homeodomain of DUX4 in Complex with a DNA aptamer containing bulge and loop

spinqualitylabelsall models 6u82, resolution 3.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6u82 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.21Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DUX4_HUMAN Facioscapulohumeral dystrophy. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death. Function DUX4_HUMAN Involved in transcriptional regulation. May regulate microRNA (miRNA) expression. Publication Abstract from PubMed 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. DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD.,Klingler C, Ashley J, Shi K, Stiefvater A, Kyba M, Sinnreich M, Aihara H, Kinter J FASEB J. 2020 Feb 5. doi: 10.1096/fj.201902696. PMID:32020675 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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