A structural mechanism of nuclear receptor biased agonism

Abstract

Efforts to decrease the adverse effects of nuclear receptor (NR) drugs have yielded experimental agonists that produce better outcomes in mice. Some of these agonists have been shown to cause different, not just less intense, on-target transcriptomic effects; however, a structural explanation for such agonist-specific effects remains unknown. Here, we show that partial agonists of the NR peroxisome proliferator-associated receptor γ (PPARγ), which induce better outcomes in mice compared to clinically utilized type II diabetes PPARγ-binding drugs thiazolidinediones (TZDs), also favor a different group of coactivator peptides than the TZDs. We find that PPARγ full agonists can also be biased relative to each other in terms of coactivator peptide binding. We find differences in coactivator–PPARγ bonding between the coactivator subgroups which allow agonists to favor one group of coactivator peptides over another, including differential bonding to a C-terminal residue of helix 4. Analysis of all available NR–coactivator structures indicates that such differential helix 4 bonding persists across other NR–coactivator complexes, providing a general structural mechanism of biased agonism for many NRs. Further work will be necessary to determine if such bias translates into altered coactivator occupancy and physiology in cells.

Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity

“…As expected, PPARγ full agonists GW1929 and pioglitazone recruited all coactivator peptides to the ligand-bound PPARγ LBD (Figure C). In contrast, the compound 11 -bound PPARγ LBD only significantly recruited the coactivator peptide RAP250 at 10 μM (Figure C), thereby also supporting the PPARγ partial agonist characteristics of compound 11 . When the concentration-dependent effect of the RAP250 coactivator recruitment was analyzed, the EC 50 values of compound 11 and pioglitazone were determined to be 19.6 and 17.7 μM, respectively (Figure D).…”

“…In contrast, the compound 11-bound PPARγ LBD only significantly recruited the coactivator peptide RAP250 at 10 μM (Figure 2C), thereby also supporting the PPARγ partial agonist characteristics of compound 11. 32 When the concentration-dependent effect of the RAP250 coactivator recruitment was analyzed, the EC 50 values of compound 11 and pioglitazone were determined to be 19.6 and 17.7 μM, respectively (Figure 2D). In this regard, the prenylated chrysin derivatives could activate PPARγ functions by recruiting RAP250, and their effects on PPARγ were significantly improved compared with those of compound 1.…”

Oxidative Stress and the Nrf2/PPARγ Axis in the Endometrium: Insights into Female Fertility

“…PPAR co-activators display a spectrum of intrinsic biological functions. These include histone modification with histone acetylases such as cAMP response element-binding protein (CREB)-binding protein (CBP/p300) and steroid receptor coactivator 1 (SRC-1) [110,111], as well as ATPases like the members of the switch/sucrose non-fermentable (SWI/SNF) complex, involved in the dynamic remodeling of chromatin [112]. Additionally, co-activators include proteins bridging the nuclear receptor and the transcription initiation machinery, such as PPAR binding protein/thyroid receptor-associated protein 220 (PBP/TRAP220) [113].…”

A unified approach to evolutionary conservation and population constraint in protein domains highlights structural features and pathogenic sites

“…The CMD cluster includes four positions that form the coactivator binding cleft, including position 104, which corresponds to the critical H3 charge-clamp residue 78 (this is R281 in STF1). In STF1, R281, F286 and L298 each interact with one or more of the conserved leucines within the coactivator LXXLL motif.…”