NECA has a unique mode of binding to the Grp94 NTD. (A) Numerous chemical shift perturbations of the NTD are observed from NECA binding. Buffer conditions: 25 mM KH2PO4 pH 7.0, 50 mM KCl, 2 mM BME, 293 K. (B) Example of residues with NECA‐specific chemical shift changes. (C) Grp94 NTD structures bound to ADP (dark gray, 1TC6) and NECA (red, 1U2O) are consistent with the unique structural consequences of NECA binding observed by NMR.