AbstractA ((1S,2R)‐2‐hydroxy‐2,3‐dihydro‐1H‐inden‐1‐yl) succinamide derivative (here referred to as Compound 12) shows significant activity toward many matrix metalloproteinases (MMPs), including MMP‐2, MMP‐8, MMP‐9, and MMP‐13. Modeling studies had predicted that this compound would not bind to ADAMTS‐5 (a disintegrin and metalloproteinase with thrombospondin motifs‐5) due to its shallow S1′ pocket. However, inhibition analysis revealed it to be a nanomolar inhibitor of both ADAMTS‐4 and −5. The observed inconsistency was explained by analysis of crystallographic structures, which showed that Compound 12 in complex with the catalytic domain of ADAMTS‐5 (cataTS5) exhibits an unusual conformation in the S1′ pocket of the protein. This first demonstration that cataTS5 can undergo an induced conformational change in its active site pocket by a molecule like Compound 12 should enable the design of new aggrecanase inhibitors with better potency and selectivity profiles.