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Those with high affinity for theophylline have the potential to serve as biosensors, crucial for tracking theophylline levels in the treatment of respiratory conditions. Despite the extensive structural characterization of the RNA theophylline aptamer, the DNA counterpart's ligand\u2010recognition mechanism has remained unclear. Here, we elucidate the DNA theophylline aptamer's ligand\u2010binding mechanism through high\u2010resolution crystal structures of its complexes with theophylline, 3\u2010methylxanthine, and hypoxanthine. Guided by these structural insights, we computationally redesigned the theophylline\u2010binding pocket via rational mutagenesis of key nucleotides, generating novel aptamers selective for adenine and prequeuosine (preQ\n                    <jats:sub>1<\/jats:sub>\n                    ) ligands. These engineered aptamers were validated through biochemical and crystallographic analyses. By integrating structural biology with computational design, our work provides a relatively simple and effective method for developing new aptamers. While this strategy does not supplant SELEX, it serves as a beneficial complement to it.\n                  <\/jats:p>","DOI":"10.1002\/anie.202504107","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T15:53:06Z","timestamp":1742313186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["From Theophylline to Adenine or preQ\n                    <sub>1<\/sub>\n                    : Repurposing a DNA Aptamer Revealed by Crystal Structure Analysis"],"prefix":"10.1002","volume":"64","author":[{"given":"Xiaowei","family":"Lin","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 510120 China"},{"name":"Department of Urology Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen 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Evaluation Sun Yat\u2010sen University  Guangzhou 510120 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Luo","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 510120 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Lu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 510120 China"},{"name":"School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou 510120 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