Large-Scale Ligand Perturbations of the Protein Conformational Landscape Reveal State-Specific Interaction Hotspots.

ABSTRACT: Protein flexibility is important for ligand binding but often ignored in drug design. Considering proteins as ensembles rather than static snapshots creates opportunities to target dynamic proteins that lack FDA-approved drugs, such as the human chaperone, heat shock protein 90 (Hsp90). Hsp90α accommodates ligands with a dynamic lid domain, yet no comprehensive analysis relating lid conformations to ligand properties is available. To date, ∼300 ligand-bound Hsp90α crystal structures are deposited in the Protein Data Bank, which enables us to consider ligand binding as a perturbation of the protein conformational landscape. By estimating binding site volumes, we classified structures into distinct major and minor lid conformations. Supported by retrospective docking, each conformation creat

SUBMITTER: Stachowski TR 

PROVIDER: S-EPMC9619398 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature