Visualizing the transiently populated closed-state of human HSP90 ATP binding domain - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2022

Visualizing the transiently populated closed-state of human HSP90 ATP binding domain

Abstract

HSP90 are abundant molecular chaperones, assisting the folding of several hundred client proteins, including substrates involved in tumor growth or neurodegenerative diseases. A complex set of large ATP-driven structural changes occurs during HSP90 functional cycle. However, the existence of such structural rearrangements in apo HSP90 has remained unclear. Here, we identify a metastable excited state in the isolated human HSP90α ATP binding domain. We use solution NMR and mutagenesis to characterize structures of both ground and excited states. We demonstrate that in solution the HSP90α ATP binding domain transiently samples a functionally relevant ATP-lid closed state, distant by more than 30 Å from the ground state. NMR relaxation enables to derive information on the kinetics and thermodynamics of this interconversion, while molecular dynamics simulations establish that the ATP-lid in closed conformation is a metastable exited state. The precise description of the dynamics and structures sampled by human HSP90α ATP binding domain provides information for the future design of new therapeutic ligands.
Fichier principal
Vignette du fichier
s41467-022-35399-8.pdf (3.13 Mo) Télécharger le fichier
Origin Publication funded by an institution
Licence

Dates and versions

hal-04025433 , version 1 (31-10-2023)

Licence

Identifiers

Cite

Faustine Henot, Elisa Rioual, Adrien Favier, Pavel Macek, Elodie Crublet, et al.. Visualizing the transiently populated closed-state of human HSP90 ATP binding domain. Nature Communications, 2022, 13 (1), pp.7601. ⟨10.1038/s41467-022-35399-8⟩. ⟨hal-04025433⟩
44 View
13 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More