Ligand-driven reorganization of the C. neoformans binding pocket. (A) Overlay of the human (light blue, 2VCI), C. albicans (red, 6CJS) and C. neoformans (orange, 7K9S) complexes with AUY922. (B) Overlay of the C. neoformans NBD in complex with AUY422 (orange, 7K9S) and RAP compounds 10 (7K9W), 18 (7K9V) and 19 (7K9U) (dark blue). (C-F) Residues L93, F125 and W128 from helices α4, α7 and strand β5, respectively, are in packing contact in the apo (6CJI, C) and AUY922 (7K9S, D) complexes, but are disrupted by the R2 aryl ring of the RAPs (7K9W, E/F). The two chains in the co-crystals of the C. neoformans NBD with 10 reveal different rotamers of the meta-methoxy aryl ring, shown in panels E and F.