Fig. 2
From: Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus
Comparison of inhibitor-bound structures for C. albicans vs human Hsp90 NBD. a Detailed view of the binding mode of SNX-2112 to C. albicans Hsp90 nucleotide-binding domain (NBD) (dark blue), overlaid with a human Hsp90α NBD structure in complex with SNX-2112 (light blue; PDB id. 4NH7). Several of the C. albicans Hsp90 residues interacting with the compound are identified, and the conformation of the 93–102 region is indicated by a dotted rectangle. Binding affinities for the compound were determined by equilibrium competition FP assay using purified human and fungal NBDs. Ki values are indicated below the structures. The mean ± SEM of three independent experiments is presented. b Detailed view of the binding mode of AUY922 to C. albicans Hsp90 NBD (orange), overlaid with a human Hsp90α NBD structure in complex with the same compound (light orange; PDB id. 2VCI). Several C. albicans Hsp90 residues interacting with the compound are identified. The helical conformation of the 93–102 region is indicated by a dotted rectangle. Hsp90 NBD binding affinities were determined as described for panel a. The mean ± SEM of three independent experiments is presented. c Inhibitor-induced conformational changes in C. albicans NBD. Ribbon representation of C. albicans Hsp90 NBD bound to Hsp90 inhibitors SNX-2112 (left image) and AUY922 (right image). Apo structure (green) is overlaid. Compounds are represented as sticks and color-coded according to heteroatom composition. A detailed view of the conformational differences in the 93–102 region between apo and SNX-2112 bound crystal structures is provided; SNX-2112 is shown as sticks and a semitransparent yellow surface. d Views from different angles of the C. albicans Hsp90 NBD in its apo and AUY922-bound states. Overlays of the crystal structures are shown in cartoon/ribbon representation. Secondary structure elements are color-coded to highlight the conformational changes associated with AUY922 binding; dotted arrows indicate the direction of the movement of secondary structure elements. The outline of the apo surface is indicated by a black line, and the AUY922 position is indicated as a semitransparent yellow sphere representation. Source data for the determination of all inhibitory constants are provided as a source data file.
