A crystal structure of the compound bound to VHL was obtained at the resolution of 1.98 Å. The well-resolved electron density allowed the identification of the eutomer. (Figure , Supplementary Table , Supplementary Figure ). The newly identified hydroxy-piperidinone motif of 1 occupies the hydroxyproline recognition site of VHL, forming conserved hydrogen bonds to Ser-111 and His-115. While the RHS motif is conserved compared to template ligand 10, ring expansion and amide inversion leads to an altered exit vector towards the LHS.