8B7I

Human HSP90 alpha ATP Binding Domain, ATP-lid open conformation, R60A

Summary for 8B7I

• Entry DOI: 10.2210/pdb8b7i/pdb
• NMR Information: BMRB: 34758
• Descriptor: HSP90AA1 protein (1 entity in total)
• Functional Keywords: chaperone, human chaperone protein, hsp90 alpha, n-terminal domain, atp binding domain, ground state, atp-lid open state
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 29934.48

Authors

Rioual, E.,Henot, F.,Favier, A.,Macek, P.,Crublet, E.,Josso, P.,Brutscher, B.,Frech, M.,Gans, P.,Loison, C.,Boisbouvier, J. (deposition date: 2022-09-30, release date: 2022-11-16, Last modification date: 2024-06-19)

Primary citation

Henot, F.,Rioual, E.,Favier, A.,Macek, P.,Crublet, E.,Josso, P.,Brutscher, B.,Frech, M.,Gans, P.,Loison, C.,Boisbouvier, J.
Visualizing the transiently populated closed-state of human HSP90 ATP binding domain.
Nat Commun, 13:7601-7601, 2022

PubMed 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.

PubMed: 36494347
DOI: 10.1038/s41467-022-35399-8

Experimental method

SOLUTION NMR