Crystal structures of SFs 2f and 2s within BCL6 were generated to further investigate the binding mode of the fragments; this used a previously published protocol. Co-crystal structures of 2f and 2s with BCL6 (solved to 1.6 Å and 1.8 Å resolution, respectively) revealed Tyr57 covalently conjugated to the fragments via a sulfonate ester, consistent with tandem MS studies for SF 2f (Fig. &). The residue Arg27 was observed to be in close proximity to the sulfonyl groups of 2f and 2s which may have catalysed the covalent modification of Tyr57 via hydrogen bonding interactions. While the meta-substitutions of the benzamides showed opposite trajectories, a common binding surface of the benzamide aryl ring was observed, suggesting that a tri-substituted aryl group might be tolerated here (Fig. ). The twisted conformation of 2s could also represent a pre-modified state of the protein-SF complex, which may have become disrupted for 2f upon covalent modification with Tyr57 to afford the extended conformation observed. The structures of GSK137 and 2s were overlaid, revealing that the two binding sites had significant overlap in the final crystallographic state (Fig. ). This suggested that 2s may have similar inhibitory action to GSK137 on the BCL6 BTB/POZ domain.