7ZVX
Crystal structure of human Annexin A2 in complex with full phosphorothioate 5-10 2'-methoxyethyl DNA gapmer antisense oligonucleotide solved at 2.4 A resolution
Summary for 7ZVX
| Entry DOI | 10.2210/pdb7zvx/pdb |
| Related | 7ZVN |
| Descriptor | Annexin A2, 2'-methoxyethyl DNA gapmer antisense oligonucleotide, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | nucleic acid binding, aso, antisense oligonucleotide, phosphorothioate, lipid binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 91744.63 |
| Authors | Hyjek-Skladanowska, M.,Anderson, B.,Mykhaylyk, V.,Orr, C.,Wagner, A.,Skowronek, K.,Seth, P.,Nowotny, M. (deposition date: 2022-05-17, release date: 2022-09-14, Last modification date: 2024-02-07) |
| Primary citation | Hyjek-Skladanowska, M.,Anderson, B.A.,Mykhaylyk, V.,Orr, C.,Wagner, A.,Poznanski, J.T.,Skowronek, K.,Seth, P.,Nowotny, M. Structures of annexin A2-PS DNA complexes show dominance of hydrophobic interactions in phosphorothioate binding. Nucleic Acids Res., 51:1409-1423, 2023 Cited by PubMed Abstract: The introduction of phosphorothioate (PS) linkages to the backbone of therapeutic nucleic acids substantially increases their stability and potency. It also affects their interactions with cellular proteins, but the molecular mechanisms that underlie this effect are poorly understood. Here, we report structural and biochemical studies of interactions between annexin A2, a protein that does not possess any known canonical DNA binding domains, and phosphorothioate-modified antisense oligonucleotides. We show that a unique mode of hydrophobic interactions between a sulfur atom of the phosphorothioate group and lysine and arginine residues account for the enhanced affinity of modified nucleic acid for the protein. Our results demonstrate that this mechanism of interaction is observed not only for nucleic acid-binding proteins but can also account for the association of PS oligonucleotides with other proteins. Using the anomalous diffraction of sulfur, we showed that preference for phosphorothioate stereoisomers is determined by the hydrophobic environment around the PS linkage that comes not only from protein but also from additional structural features within the ASO such as 5-Me groups on cytosine nucleobases. PubMed: 36124719DOI: 10.1093/nar/gkac774 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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