Copper plays a vital role in fundamental cellular functions, and its concentration in the cell must be tightly regulated, as dysfunction of copper homeostasis is linked to severe neurological diseases and cancer. Indeed, small-molecules targeting Cu-chaperones Atox1, Atp7B and CCS, which shuttle the metal from the Cu transporter Ctr1 to the appropriate cellular protein/destination, were discovered to be active/selective in vivo against distinct cancer types. Moreover, the Cu-cycle provides a viable route for the selective uptake ofradioimaging/therapeutic copper-complexes via Ctr1.
In this project we aim at unraveling the mechanism of in cell Cu(I) uptake and distribution via all atom simulations at classical and quantum-classical level to design novel radioactive compound for diagnostic and therapeutic purposes. The project is financed by an AIRC fellowship G. Favariga Awarded to Dr. J. Aupic. Project is in collaboration with Prof. S. Ruthstein, Bar Ilan University, Tel Aviv Israel, and Dr. Fabio Lapenta, University of Nova Gorica, Slovenia.
Key publications
Janos, P., Aupic, J., Ruthstein, S. & Magistrato, A. The Conformational Plasticity of the Selectivity Filter Methionines Controls the In-Cell Cu(I) Uptake through the CTR1 transporter. bioRxiv (2021). doi:10.1101/2021.11.04.467269
Qasem, Z. et al. The pivotal role of MBD4-ATP7B in the human Cu(i) excretion path as revealed by EPR experiments and all-atom simulations. Metallomics 11, 1288–1297 (2019).
Magistrato, A., Pavlin, M., Qasem, Z. & Ruthstein, S. Copper trafficking in eukaryotic systems: current knowledge from experimental and computational efforts. Curr. Opin. Struct. Biol. 58, 26–33 (2019).
Magistrato Lab 