The The crystal structure of Chimera 7 showed the presence of a HEPES molecule from the crystallization buffer at the active site (Figure ). The sulfonyl group makes hydrogen bonds to P-loop residues and to Arg221, analogous to those of a phosphate ester substrate, and the WPDloop is in the closed conformation. The alkyl ring of the HEPES molecule is in a position that would clash with the side chain of F182 in native PTP1B. Other details of HEPES interactions are shown and discussed in the Supporting Information.