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Cyclic Phosphopeptides to Rationalize the Role of Phosphoamino Acids in Uranyl Binding to Biological Targets
Author(s) -
Starck Matthieu,
Laporte Fanny A.,
Oros Stephane,
Sisommay Nathalie,
Gathu Vicky,
Solari Pier Lorenzo,
Creff Gaëlle,
Roques Jérôme,
Den Auwer Christophe,
Lebrun Colette,
Delangle Pascale
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605481
Subject(s) - uranyl , chemistry , moiety , combinatorial chemistry , peptide , binding site , stereochemistry , biochemistry , organic chemistry , ion
The specific molecular interactions responsible for uranium toxicity are not yet understood. The uranyl binding sites in high‐affinity target proteins have not been identified yet and the involvement of phosphoamino acids is still an important question. Short cyclic peptide sequences, with three glutamic acids and one phosphoamino acid, are used as simple models to mimic metal binding sites in phosphoproteins and to help understand the mechanisms involved in uranium toxicity. A combination of peptide design and synthesis, analytical chemistry, extended X‐ray absorption fine structure (EXAFS) spectroscopy, and DFT calculations demonstrates the involvement of the phosphate group in the uranyl coordination sphere together with the three carboxylates of the glutamate moieties. The affinity constants measured with a reliable analytical competitive approach at physiological pH are significantly enhanced owing to the presence of the phosphorous moiety. These findings corroborate the importance of phosphoamino acids in uranyl binding in proteins and the relevance of considering phosphoproteins as potential uranyl targets in vivo.