Fig. 3

Fig. 3

a Schematic of design method 2: anchors are extended, and the new peptide chain is closed inside the protein pocket. b In this round of designs, a Trp residue was added as an anchor in addition to SHA, and the backbone orientation of SHA and the preceding residue were fixed to orient two structural waters at the interface. c Chemical structure of des2.1.1. d des2.1.1 has an IC₅₀ value of 16.3 nM against HDAC2 and slight preference for HDAC6 over HDAC2 (Source Data are provided as a Source Data file). e Crystal structure of des2.1.1 (PDB ID: 6WI3, light gray) shows a conformation consistent with the designed model for SHA, Trp, and waters at the interface; however, the rest of the peptide shows higher flexibility. The original model is shown in dark gray. f The binding-competent backbone conformation from the crystal structure (light gray) is different from the NMR structure of the peptide in solution (dark gray), suggesting a conformational change upon binding. Both of these structures differ from the design model. The sidechains, except for Trp are removed for clarity. g The flexibility of des2.1.1 is consistent with conformational sampling results, suggesting that this peptide can sample a number of different conformational states far from the designed model (Source Data are provided as a Source Data file).