To test this hypothesis and aim to capture more bona fide binding interactions for 13, we decided to pursue a co-crystallization strategy next. SBC was co-crystallised in the presence of 13 and we successfully solved the structure (Figure ). The liganded co-crystal structure had a different space group from the apo structure, which comprised of four protomers in the asymmetric unit in comparison to a single protomer for the apo crystal form. The ligand was bound in all four subunits, and in one of the protomers, we observed unusual electron density towards the opposite direction from the HT channel. Closer inspection of the omit map electron density in this region identified a covalent bond between the terminal carbon of the allyl group of the ligand and Cys111 at the EF loop (Figure ). This observation was surprising and unexpected because allyl groups are not considered strong electrophiles and are not known nor used to readily react with cysteine residues, unless the thiol-allyl reaction is radically induced . Nonetheless, this serendipitous finding suggested that Cys111, which is in the flexible EF loop of the SOCS2 SH2 domain, could potentially be targeted as a reactive nucleophilic protein residue. Curiously, our previous crystallographic work had identified Cys111 as highly reactive site to electrophilic modifications with cacodylate from the crystallographic buffer .