High-affinity, selective ligands are sought for a variety of biomolecules but are particularly difficult to generate in the protein–protein interaction space. Rhodium(II) conjugates provide a structure-based approach to improved affinity and specificity for targeting protein–protein interactions such as SH3 domains. In this study of small-molecule–rhodium conjugates, we report a potent ligand 4b (K_d of 27 nM) for the Lyn SH3 domain, based on an aminoquinoline fragment. The results demonstrate robust affinity gains possible from even modest small-molecule leads through cooperative inorganic–organic binding, based on specific histidine interactions. A docking study sheds light on the structural basis of binding and supports a previously proposed binding model.