Structural Insight Into a Human H Ferritin@Gold‐Monocarbene Adduct: Aurophilicity Revealed in a Biological Context

Abstract Human H ferritin (HuHf) has excellent potential as a nanocarrier for the selective delivery of anticancer metal‐based drugs to tumor cells. Here, we addressed the interaction of the gold monocarbene compound Au(NHC)Cl with HuHf by electrospray ionization‐mass spectrometry (ESI‐MS) measurements, which provide the metalation state of the protein subunits and demonstrate the involvement of protein cysteines in gold binding. The adduct between Au(NHC)Cl and HuHf was studied by cryo‐EM measurements, resulting in a high‐resolution 3D density map at 1.51 Å. The cryo‐EM structure shows a novel tetranuclear gold(I) cluster, located in a surface pocket of each subunit where it is bound to Cys90 and Cys102. The short inter‐metal distances are diagnostic of the occurrence of aurophilic interactions. The present work demonstrates the usefulness of cryo‐EM to investigate the interactions between metal‐based drugs and their protein targets/carriers, also leveraging the strong signal of transition metal ions.