Visualizing the transiently populated closed-state of human HSP90 ATP binding domain.
Faustine HenotElisa RioualAdrien FavierPavel MacekElodie CrubletPierre JossoBernhard BrutscherMatthias FrechPierre GansClaire LoisonJerome BoisbouvierPublished in: Nature communications (2022)
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.
Keyphrases
- heat shock protein
- heat shock
- heat stress
- molecular dynamics simulations
- endothelial cells
- high resolution
- induced pluripotent stem cells
- magnetic resonance
- pluripotent stem cells
- dna binding
- healthcare
- single molecule
- binding protein
- lymph node
- oxidative stress
- solid state
- molecular docking
- transcription factor
- energy transfer