6XHD

Structure of Prolinyl-5'-O-adenosine phosphoramidate

Summary for 6XHD

• Entry DOI: 10.2210/pdb6xhd/pdb
• Descriptor: 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)
• Functional Keywords: rnase a complex, amino acid release, prodrug, rna binding protein
• Biological source: Bos taurus (Bovine)
• Total number of polymer chains: 2
• Total formula weight: 28018.26

Authors

Pallan, P.S.,Egli, M. (deposition date: 2020-06-18, release date: 2021-03-17, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.51 Å)