Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor
(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.
(Less)
- author
- organization
- publishing date
- 2020-07-01
- 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
-
- scopus:85090073764
- pmid:32832645
- 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
- 2024-09-05 04:36:57
@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}}, }