4Y60

Structure of SOX18-HMG/PROX1-DNA

Summary for 4Y60

• Entry DOI: 10.2210/pdb4y60/pdb
• Descriptor: Transcription factor SOX-18, DNA (5'-D(*CP*AP*CP*TP*AP*GP*CP*AP*TP*TP*GP*TP*CP*TP*GP*GP*G)-3'), DNA (5'-D(*GP*CP*CP*CP*AP*GP*AP*CP*AP*AP*TP*GP*CP*TP*AP*GP*T)-3'), ... (4 entities in total)
• Functional Keywords: transcription factor, sox, protein-dna, transcription-dna complex, transcription/dna
• Biological source: Mus musculus (Mouse); More
• Cellular location: Nucleus: P43680
• Total number of polymer chains: 3
• Total formula weight: 20186.19

Authors

Narasimhan, K.,Prokoph, N.,Kolatkar, P.,Robinson, H.,Jauch, R. (deposition date: 2015-02-12, release date: 2016-03-02, Last modification date: 2024-03-20)

Primary citation

Klaus, M.,Prokoph, N.,Girbig, M.,Wang, X.,Huang, Y.H.,Srivastava, Y.,Hou, L.,Narasimhan, K.,Kolatkar, P.R.,Francois, M.,Jauch, R.
Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction.
Nucleic Acids Res., 44:3922-3935, 2016

PubMed Abstract: The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75Å presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis.

PubMed: 26939885
DOI: 10.1093/nar/gkw130

Experimental method

X-RAY DIFFRACTION (1.75 Å)