What does this research mean for the field?

Accelerating the transfer of Cu(II) ions from inert ATCUN complexes requires agents, such as histidine or His-Leu dipeptide, that possess both high thermodynamic affinity and a specific two-coordinate amine/imidazole structural motif. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

This research aims to identify small molecules that can effectively mobilize Cu(II) from inert ATCUN complexes.

June 14, 2026Open Access

Agents mobilizing cu(II) from the inert ATCUN complex need both high affinity and a specific chelating structure

Key Points

This research aims to identify small molecules that can effectively mobilize Cu(II) from inert ATCUN complexes.
Screened small molecules with different Cu(II) binding groups for their ability to accelerate Cu(II) ion transfer.
Utilized Aβ 4–16 peptide and EDTA as models for Cu(II) binding and transfer dynamics.
Identified structures with two-coordinate amine/imidazole motifs as key to enhancing transfer kinetics.
Histidine and His-Leu dipeptide significantly increased Cu(II) transfer rate from Aβ 4–16 to EDTA.
Proved the necessity of a specific chelating structure for effective mobilization of Cu(II).
Results indicate potential for exploring physiological copper transfers further.

Abstract

ATCUN motifs at the N-termini of defined and putative Cu(II) handling proteins provide tight Cu(II) ion binding and prevent the unwanted redox activity of the ion. On the other hand, the Cu(II)-ATCUN complexes exhibit slow or very slow (hours to days) kinetics of Cu(II) exchange with other, ATCUN and non-ATCUN chelators. We chose a number of small molecules involved in copper physiology, bearing different Cu(II) binding groups and screened their ability to accelerate the Cu(II) ion transfer from Aβ 4–16 , an ATCUN β-amyloid model peptide to EDTA serving as a thermodynamic Cu(II) sink representing copper receptors and transporters. The transfer was enhanced specifically by histidine and His-Leu dipeptide, sharing a two-coordinate amine/imidazole structural motif assisted by an oxygen donor and providing sufficient thermodynamic stability of Cu(II) ion binding. This result is consistent with the reaction model including a structurally specific ternary intermediate, and paves a way for further investigations of physiological copper transfers.

Read Full Paperexternally

Bookmark

View Full Paper

Cite This Study

Szczerba et al. (Mon,) studied this question.

synapsesocial.com/papers/6a2e4524b1cc60ccdea8a716 https://doi.org/https://doi.org/10.1016/j.jinorgbio.2026.113387

Bookmark

View Full Paper