Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor

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.

Carlström, G.Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)chem-gcl (author)
Gunnarsson, A.AstraZeneca, Sweden (author)
Weininger, U.Lund University,Lunds universitet,Biofysikalisk kemi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biophysical Chemistry,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)bpc-uiw (author)
Tångefjord, S.AstraZeneca, Sweden (author)
Ullah, V.AstraZeneca, Sweden (author)
Lepistö, M.AstraZeneca, Sweden (author)
Karlsson, U.AstraZeneca, Sweden (author)
Papavoine, T.AstraZeneca, Sweden (author)
Edman, K.AstraZeneca, Sweden (author)
Akke, M.Lund University,Lunds universitet,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)fkm2-mak (author)
AstraZeneca, SwedenCentrum för analys och syntes (creator_code:org_t)

In:Science Advances: American Association for the Advancement of Science (AAAS)6:292375-2548

By the author/editor: Köhler, Christia ...; Carlström, G.; Gunnarsson, A.; Weininger, U.; Tångefjord, S.; Ullah, V.; show more...; Lepistö, M.; Karlsson, U.; Papavoine, T.; Edman, K.; Akke, M.; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biophysics

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