Fig. 1

Fragment-based lead generation of Rheb-binding small molecules. a 1D ¹H saturation transfer difference (STD) NMR spectra of 1 in presence and absence of C-terminal truncated Rheb. b 2D ¹H–¹⁵N heteronuclear multi-quantum coherence (HMQC) NMR spectra of ¹⁵N-labeled Rheb (200 µM) alone (black) and in presence of 1 mM 1 (red) showing key residues of the switch II domain. c Structure of Rheb showing side-chains of residues where significant chemical shift perturbations were observed upon binding 1. NMR structure of GDP-bound Rheb from Karassek et al.³⁷ shown. d 1.56 Å X-ray crystal structure of GDP-Rheb with 1 bound in the switch II domain. Side-chains of residues within 4 Å of 1 are shown