Comparison of activity, structure, and dynamics of SF-1 and LRH-1 complexed with small molecule modulators

Cato, Michael L.; D’Agostino, Emma H.; Spurlin, Racheal M.; Flynn, Autumn R.; Cornelison, Jeffery L.; Johnson, Alyssa M.; Fujita, Reiko; Abraham, Susamma; Jui, Nathan T.; Ortlund, Eric A.

doi:10.1016/j.jbc.2023.104921

Cited by 6 publications

(4 citation statements)

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“…We found ∆∆G positively associated with the ability of our set of 58 hit compounds to regulate full-length LRH-1 in cellbased assays. Network analyses suggest the position of Helix 6 as a structural element that may contribute to the relationship between ∆∆G and ligand-mediated LRH-1 regulation in cells, consistent with analyses by independent groups [37,64,70,71,[74][75][76]. The data presented here suggest a role for Helix 6 in ligand-mediated regulation of LRH-1, similar to other studies which have applied comparative crystallography, MD simulations and network analyses [37,64,70,71,[74][75][76].…”

Section: Introductionsupporting

confidence: 88%

“…Network analyses suggest the position of Helix 6 as a structural element that may contribute to the relationship between ∆∆G and ligand-mediated LRH-1 regulation in cells, consistent with analyses by independent groups [37,64,70,71,[74][75][76]. The data presented here suggest a role for Helix 6 in ligand-mediated regulation of LRH-1, similar to other studies which have applied comparative crystallography, MD simulations and network analyses [37,64,70,71,[74][75][76]. The ∆∆G metric can help prioritize hit compounds for expensive secondary screening, which can hasten LRH-1 compound development.…”

Section: Introductionsupporting

confidence: 74%

“…Perhaps most importantly, convincing work from the Ortlund lab at Emory and now the Okafor lab at Penn State [74] have used extensive MD simulations, network analyses and direct comparisons of different ligand-bound structures of LRH-1 to independently suggest an important role for Helix 6 in ligand-regulated activation of LRH-1 [37,64,70,71,[74][75][76], linking the mobility of residues at the entrance to the ligand binding pocket near Helix 6 to synthetic small molecule-induced LRH-1 activity [76]. The volume of the ligand-binding pocket is smaller in structures bound to synthetic small molecules vs. phospholipids [64], consistent with the docking studies presented here, as well as hydrogen-deuterium exchange data [37,64,71,76], MD simulations [64,70,71,[74][75][76] and other network analyses [70,76]. Together, these studies support a role for Helix 6 is an important element in translating ligand binding events from the binding pocket to the transcriptional coregulator [70,71].…”

Section: Discussionmentioning

confidence: 99%

“…We then correlated those docking results retrospectively with published cell-based functional data from our previous study (439 total functional assay measurements) [1]. We found that docking to the full-length model of LRH-1 [73] predicts different binding positions for compounds active on full-length LRH-1, which were closer to the entrance of the ligand binding pocket and Helix 6, an important helix that helps mediate ligand activation of LRH-1 [37,64,70,71,[74][75][76]. The scores of compounds docked to full-length LRH-1 or the isolated LBD did not correlate with LRH-1 regulation in wet lab assays, however several compounds had large differences in docking scores (∆G) to the full-length vs. isolated LBD of LRH-1, an arbitrary metric we call ∆∆G.…”

Section: Introductionmentioning

confidence: 99%

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A novel heuristic of rigid docking scores positively correlates with full-length nuclear receptor LRH-1 regulation.

Haratipour,

Foutch,

Blind

2024

Preprint

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The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2) is a ligand-regulated transcription factor and validated drug target for several human diseases. LRH-1 activation is regulated by small molecule ligands, which bind to the ligand binding domain (LBD) within the full-length LRH-1. We recently identified 57 compounds that bind LRH-1, and unexpectedly found these compounds regulated either the isolated LBD, or the full-length LRH-1 in cells, with little overlap. Here, we correlated compound binding energy from a single rigid-body scoring function with full-length LRH-1 activity in cells. Although docking scores of the 57 hit compounds did not correlate with LRH-1 regulation in wet lab assays, a subset of the compounds had large differences in binding energy docked to the isolated LBD vs. full-length LRH-1, which we used to empirically derive a new metric of the docking scores we call "ΔΔG". Initial regressions, correlations and contingency analyses all suggest compounds with high ΔΔG values more frequently regulated LRH-1 in wet lab assays. We then docked all 57 compounds to 18 crystal structures of LRH-1 to obtain averaged ΔΔG values, which robustly and reproducibly associated with full-length LRH-1 activity in cells. Network analyses on the 18 crystal structures of LRH-1 suggest unique communication paths exist between the subsets of LRH-1 crystal structures that produced high vs. low ΔΔG values, identifying a structural relationship between ΔΔG and the position of Helix 6, a previously established regulatory helix important for LRH-1 regulation. Together, these data suggest computational docking can be used to quickly calculate ΔΔG, which positively correlated with the ability of these 57 hit compounds to regulate full-length LRH-1 in cell-based assays. We propose ΔΔG as a novel computational tool that can be applied to LRH-1 drug screens to prioritize compounds for secondary screening.Although docking scores of the 57 hit compounds did not correlate with LRH-1 regulation in wet lab assays, a subset of the compounds had large differences in binding energy docked to the isolated LBD vs. full-length LRH-1, which we used to empirically derive a new metric of the docking scores we call "ΔΔG". Initial regressions, correlations and contingency analyses all suggest compounds with high ΔΔG values more frequently regulated LRH-1 in wet lab assays. We then docked all 57 compounds to 18 crystal structures of LRH-1 to obtain averaged ΔΔG values, which robustly and reproducibly associated with full-length LRH-1 activity in cells. Network analyses on the 18 crystal structures of LRH-1 suggest unique communication paths exist between the subsets of LRH-1 crystal structures that produced high vs. low ΔΔG values, identifying a structural relationship between ΔΔG and the position of Helix 6, a previously established regulatory helix important for LRH-1 regulation. Together, these data suggest computational docking can be used to quickly calculate ΔΔG, which positively correlated with the ability of these 57 hit compounds to regulate full-length LRH-1 in cell-based assays. We propose ΔΔG as a novel computational tool that can be applied to LRH-1 drug screens to prioritize compounds for secondary screening.

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