Hsp90 chaperones have an energetic hot‐spot for binding inhibitors

Abstract

Although Hsp90-family chaperones have been extensively targeted with ATPcompetitive inhibitors, it is unknown whether high affinity is achieved from a few highly stabilizing contacts or from many weaker contacts within the ATPbinding pocket. A large-scale analysis of Hsp90α:inhibitor structures shows that inhibitor hydrogen-bonding to a conserved aspartate (D93 in Hsp90α) stands out as most universal among Hsp90 inhibitors. Here we show that the D93 region makes a dominant energetic contribution to inhibitor binding for both cytosolic and organelle-specific Hsp90 paralogs. For inhibitors in the resorcinol family, the D93:inhibitor hydrogen-bond is pH-dependent because the associated inhibitor hydroxyl group is titratable, rationalizing a linked

PlayMolecule Glimpse: Understanding Protein–Ligand Property Predictions with Interpretable Neural Networks

“…Additionally, the complex possesses few features that facilitate tight binding, mainly π-stacking and a hydrogen bond with a conserved aspartate (D93)–a very frequent interaction among HSP90 inhibitors. 31 This helped us to relate the predictions to structural features of the complex.…”

“… This well studied oncology target has been a subject of numerous structure based virtual screening campaigns. , In the analyzed example, HSP90 forms a potent complex with an analogue of benzamide tetrahydro-4H-carbazol-4-one (SNX), with an affinity of 290 nM. Additionally, the complex possesses few features that facilitate tight binding, mainly π-stacking and a hydrogen bond with a conserved aspartate (D93)–a very frequent interaction among HSP90 inhibitors . This helped us to relate the predictions to structural features of the complex.…”