Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor

Köhler, Christian; Carlström, Göran; Gunnarsson, Anders; Weininger, Ulrich; Tångefjord, Stefan; Ullah, Victoria; Lepistö, Matti; Karlsson, Ulla; Papavoine, Tineke; Edman, K. A. P.; Akke, Mikael

doi:10.1126/sciadv.abb5277

Cited by 35 publications

(74 citation statements)

References 47 publications

(104 reference statements)

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“…In this context, the motility of helix H12, a structural element that bridges the two binding sites, is deemed a key feature for the modulation of the allosteric signal. 20 In this study, we adopted a multidisciplinary approach to unravel the molecular mechanisms that control the allosteric signal transmission between the AF-2 docking site and the LBP.…”

Section: Discussionmentioning

confidence: 99%

“…Here, a large helix H12 conformational change is not expected, because the agonist-like conformation is always preferred, as demonstrated by X-ray structural data 16,21 . However, we propose that the different flexibility of Trp600 captured in our MD simulations might represent one of the possible mechanical switches used to fine-tune the structural state of the helix H12 and, consequently, the functional response, as observed in NMR experiments of TIF2/GR/Dex and PRGC1/GR/Dex complexes 20 . MD trajectories' points projected along the distance between the Trp600 N1 atom and Gln760 O1 atom (i.e., Distance Trp600-Gln760, X axes) and along the distance between the Gln597 N2 atom and Gln760 O1 atom (i.e., Distance Gln597-Gln760, Y axes).…”

Section: Figure 2 Intrinsic Dynamics Of Tif2/gr/dex and Prgc1/gr/dex Complexesmentioning

confidence: 90%

“…The conformation of the AF-2 surface will, in turn, drive coregulator recruitment to DNA and elicit a specific biological response 14,15 . Interestingly, experimental studies show that coregulator peptides with high binding affinity to GRLBD, such as PRGC1, more efficiently restrict the conformational space of the helix H12 compared to other coregulator peptides, such as TIF2 20 . Here, we investigated the dynamical aspect of the helix H12/peptide interaction to evaluate how different peptide sequences stabilize the helix H12.…”

Section: Figure 5 Mechanism That Controls the Dynamics Of 'Q597w600q760-triad' A) Distance With Time Betweenmentioning

confidence: 99%

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Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Sala¹,

Gunnarsson²,

Edman³

et al. 2021

Preprint

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<div>Glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the</div><div>transcription of specific genes. There is a known allosteric cross-talk between the ligand and coregulator binding</div><div>sites within the GR ligand binding domain that is crucial for the control of the functional response. However, the</div><div>molecular mechanisms underlying such an allosteric control remain elusive. Here, molecular dynamics (MD)</div><div>simulations, bioinformatic analysis and biophysical measurements are integrated to capture the structural and</div><div>dynamic features of the allosteric cross-talk within GR. We identified a network of evolutionarily conserved</div><div>residues that enables the allosteric signal transduction, in agreement with experimental data. MD simulations</div><div>clarify how such network is dynamically interconnected and offer a mechanistic explanation of how the different</div><div>peptides affect the intensity of the allosteric signal. This study provides useful insights to elucidate the GR</div><div>allosteric regulation, ultimately, posing the foundation for designing novel drugs.</div>

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Section: Discussionmentioning

confidence: 99%

Section: Figure 2 Intrinsic Dynamics Of Tif2/gr/dex and Prgc1/gr/dex Complexesmentioning

confidence: 90%

Section: Figure 5 Mechanism That Controls the Dynamics Of 'Q597w600q760-triad' A) Distance With Time Betweenmentioning

confidence: 99%

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Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Sala¹,

Gunnarsson²,

Edman³

et al. 2021

Preprint

Self Cite

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“…For example, in the absence of ligand, the PPARγ LBD is conformationally dynamic, samples multiple conformation, and binding of an agonist stabilizes the LBD in an active conformation to a degree correlated with the activity of the ligand (18,(23)(24)(25). The association between ligand-bound NR LBD conformation and graded function is evidence for conformational selection in the mechanism of NR ligand activity (13,15,(19)(20)(21)(22)53). However, these studies only address the functional mechanism of the ligand-bound state; they do not address the mechanism of ligand binding.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, ligand binding to nuclear receptors is often described to induce an active conformation (4,(11)(12)(13)(14)(15)(16). However, there is evidence from NMR studies on PPARγ that in the absence of ligand the apo-LBD exchanges between transcriptionally active and transcriptionally inactive/repressive conformations (17) suggesting a role for conformational selection in the ligand binding mechanism of NR agonists, which are thought to stabilize an active conformation from a dynamic ensemble of active and inactive/repressive conformations (15,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Taken together, these observations stem from the ability of the ligand-bound NR LBD to exert specific functions such as coactivator interaction and transcription, but not directly on the mechanism of ligand binding to the orthosteric pocket.…”

Section: Introductionmentioning

confidence: 99%

Structural Mechanism Underlying Ligand Binding and Activation of PPARγ

Shang

Kojetin

2020

Preprint

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Ligands bind to an occluded orthosteric pocket within the nuclear receptor (NR) ligand-binding domain (LBD), but experimentally it remains unclear whether ligand binding proceeds through induced fit or conformational selection mechanisms. Using NMR spectroscopy lineshape analysis, we show that ligand binding to the peroxisome proliferator-activated receptor gamma (PPARγ) LBD involves a two-step induced fit mechanism including an initial fast step followed by slow conformational change. Surface plasmon resonance and isothermal titration calorimetry heat capacity analysis support the fast kinetic binding step and the conformational change after binding step. The putative initial ligand binding pose is suggested in several crystal structures of PPARγ LBD where a ligand is bound to a surface pore formed by helix 3, the β-sheet, and the Ω loop; one of several ligand entry sites suggested in previous targeted and unbiased molecular simulations. These findings, when considered with a recent NMR study showing the activation function-2 (AF-2) helix 12 exchanges in and out of the orthosteric pocket in apo/ligand-free PPARγ, suggest an activation mechanism whereby agonist binding occurs through an initial encounter complex with the LBD followed by transition of the ligand into the orthosteric pocket concomitant with a conformational change resulting in a solvent-exposed active helix 12 conformation.

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Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Pang

Zhang

et al. 2021

Advanced Science

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Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function‐2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure‐based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP‐19 exhibits the best anti‐inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor‐kappa B signaling pathway, which is comparable to that of DEX. HP‐19 also does not induce adverse effect‐related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

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Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor

Cited by 35 publications

References 47 publications

Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Structural Mechanism Underlying Ligand Binding and Activation of PPARγ

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

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