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Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor

Köhler, Christian ; Carlström, G. LU ; Gunnarsson, A. ; Weininger, U. LU ; Tångefjord, S. ; Ullah, V. ; Lepistö, M. ; Karlsson, U. ; Papavoine, T. and Edman, K. , et al. (2020) In Science Advances 6(29).
Abstract

Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes... (More)

Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. Our results provide key insights that should aid in the design of mechanistically differentiated ligands.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
6
issue
29
article number
eabb5277
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:32832645
  • scopus:85090073764
ISSN
2375-2548
DOI
10.1126/sciadv.abb5277
language
English
LU publication?
yes
id
4d4be530-c154-4c81-bd19-7a731ca95e7c
date added to LUP
2020-09-24 11:43:06
date last changed
2021-04-06 02:52:46
@article{4d4be530-c154-4c81-bd19-7a731ca95e7c,
  abstract     = {<p>Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. Our results provide key insights that should aid in the design of mechanistically differentiated ligands.</p>},
  author       = {Köhler, Christian and Carlström, G. and Gunnarsson, A. and Weininger, U. and Tångefjord, S. and Ullah, V. and Lepistö, M. and Karlsson, U. and Papavoine, T. and Edman, K. and Akke, M.},
  issn         = {2375-2548},
  language     = {eng},
  month        = {07},
  number       = {29},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Advances},
  title        = {Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor},
  url          = {http://dx.doi.org/10.1126/sciadv.abb5277},
  doi          = {10.1126/sciadv.abb5277},
  volume       = {6},
  year         = {2020},
}