6XHD

Structure of Prolinyl-5'-O-adenosine phosphoramidate

6XHD の概要

• エントリーDOI: 10.2210/pdb6xhd/pdb
• 分子名称: Ribonuclease pancreatic, POTASSIUM ION, (2~{S})-1-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]pyrrolidine-2-carboxylic acid, ... (5 entities in total)
• 機能のキーワード: rnase a complex, amino acid release, prodrug, rna binding protein
• 由来する生物種: Bos taurus (Bovine)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28018.26

構造登録者

Pallan, P.S.,Egli, M. (登録日: 2020-06-18, 公開日: 2021-03-17, 最終更新日: 2024-11-20)

主引用文献

Jovanovic, D.,Tremmel, P.,Pallan, P.S.,Egli, M.,Richert, C.
The Enzyme-Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid.
Angew.Chem.Int.Ed.Engl., 59:20154-20160, 2020

PubMed Abstract: Phosphoramidates composed of an amino acid and a nucleotide analogue are critical metabolites of prodrugs, such as remdesivir. Hydrolysis of the phosphoramidate liberates the nucleotide, which can then be phosphorylated to become the pharmacologically active triphosphate. Enzymatic hydrolysis has been demonstrated, but a spontaneous chemical process may also occur. We measured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with a half-life time as short as 2.4 h for Pro-AMP in ethylimidazole-containing buffer at 37 °C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP. Crystal structures of Gly-AMP, Pro-AMP, βPro-AMP and Phe-AMP bound to RNase A as crystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate, helping to explain this reactivity. Our results are significant for the design of new antiviral prodrugs.

PubMed: 32757352
DOI: 10.1002/anie.202008665

実験手法

X-RAY DIFFRACTION (1.51 Å)