MM molecular dynamics simulations. The prepared E-R systems were initially energy minimized using molecular mechanics (MM), with positional harmonic restraints and a force constant of 50 kcal mol -1 Å -2 applied to all heavy atoms of the solute. This removed any bad contacts in the docking poses. In the initial MD simulations, the temperature of the systems was gradually increased to 310 K over 100 ps, and then was kept constant for another 100 ps of NVT simulation. The temperature was controlled using the Langevin thermostat with the collision frequency of 2 ps -1 . In the second step of the relaxation phase, the systems were simulated at 310 K over 100 ps at a constant pressure of 1 bar (NPT), allowing the density of the box to equilibrate using the Berendsen barostat. In both steps of the relaxation, the harmonic positional restraints with a force constant of 50 kcal mol -1 Å -2 were kept only on heavy atoms of residues directly bound to the zinc ion including the metal ion to avoid any non-physical changes of the metal coordination site as a result of the MM force field description. All MM MD simulations were performed using the pmemd.cuda module of the AMBER18 software package. QM/MM molecular dynamics simulations. After equilibration of the systems with MM MD, unrestrained quantum-mechanics/molecular-mechanics (QM/MM) minimization was carried out for each complex. The third-order extension of the self-consistent-charge density functional tight-binding (SCC-DFTB3) method was used to describe the QM region. The QM region consisted of the Zn 2+ ion, the catalytic water molecule, and the sidechains of Glu465, Glu431, His464, His468, Glu487 and Tyr549. In addition, for the IRAP complex with angiotensin IV, the peptide N-terminus valine residue and the neighboring tyrosine residue backbone were included in the QM region. In the case of the complex with oxytocin, the QM region included the cysteine residue, tyrosine residue backbone and the sidechain of the cysteine connected to the scissile cysteine residue by a disulfide bridge. Details about the reaction coordinate and QM/MM MD setup can be found in the SI.