Partial Agonists Activate PPARγ Using a Helix 12 Independent Mechanism

Bruning, John B.; Chalmers, Michael J.; Prasad, Swati; Busby, Scott A.; Kamenecka, Theodore M.; He, Yuanjun; Nettles, K.W.; Griffin, Patrick R.

doi:10.1016/j.str.2007.07.014

Cited by 350 publications

(487 citation statements)

References 49 publications

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“…In fact, it is a partial agonist of PPARc with a weaker transcriptional activity [52][53][54]. This relationship is in agreement with our previous findings regarding two enantiomeric ureidofibrate derivatives complexed with PPARc, showing partial and full agonism, respectively, toward this nuclear receptor [52].…”

Section: Docking Of Compounds 2a and 2b Into Pparc Binding Pocketsupporting

confidence: 92%

“…9D). Interestingly, this compound makes no direct contacts with H12 residues, a hallmark of traditional TZDs, but preferentially stabilizes H3 through closer hydrophobic contacts or H-bonds made with residues of this helix (S289, F282, Q283 and Q286), likely affecting coactivator recruitment and transactivation potential [52][53][54]. Consistently, compound 2B may be considered a PPARc partial agonist and indeed displays a weaker transactivation profile than 2A (Fig.…”

Section: Discussionmentioning

confidence: 76%

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The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Zurlo

Ziccardi

Votino

et al. 2016

Biochemical Pharmacology

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a b s t r a c tCladosporols are secondary metabolites from Cladosporium tenuissimum characterized for their ability to control cell proliferation. We previously showed that cladosporol A inhibits proliferation of human colon cancer cells through a PPARc-mediated modulation of gene expression. In this work, we investigated cladosporol B, an oxidate form of cladosporol A, and demonstrate that it is more efficient in inhibiting HT-29 cell proliferation due to a robust G0/G1-phase arrest and p21 waf1/cip1 overexpression. Cladosporol B acts as a PPARc partial agonist with lower affinity and reduced transactivation potential in transient transfections as compared to the full agonists cladosporol A and rosiglitazone. Site-specific PPARc mutants and surface plasmon resonance (SPR) experiments confirm these conclusions. Cladosporol B in addition displays a sustained proapoptotic activity also validated by p21 waf1/cip1 expression analysis in the presence of the selective PPARc inhibitor GW9662. In the DMSO/H 2 O system, cladosporols A and B are unstable and convert to the ring-opened compounds 2A and 2B. Finally, docking experiments provide the structural basis for full and partial PPARc agonism of 2A and 2B, respectively. In summary, we report here, for the first time, the structural characteristics of the binding of cladosporols, two natural molecules, to PPARc. The binding of compound 2B is endowed with a lower transactivation potential, higher antiproliferative and proapoptotic activity than the two full agonists as compound 2A and rosiglitazone (RGZ).

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Section: Docking Of Compounds 2a and 2b Into Pparc Binding Pocketsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 76%

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Zurlo

Ziccardi

Votino

et al. 2016

Biochemical Pharmacology

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“…Structural characterization of indeglitazar bound to the 3 PPARs revealed that, for PPAR␦ and PPAR␥, a single water molecule was recruited into the signaling interface from ligand to receptor. Interestingly, the 4 aromatic residues of the signaling tetrad in the PPAR␥-indeglitazar co-structure overlap closely with the same set of residues observed in the complex of PPAR␥ with another partial agonist, MRL20 (25). However, whereas MRL20 shows a response of Ϸ80% relative to rosiglitazone, indeglitazar is more substantively reduced to Ϸ45%.…”

Section: Discussionsupporting

confidence: 53%

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Artis¹,

Lin²,

Zhang³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

134

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In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with highthroughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPAR␣, PPAR␥, and PPAR␦. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPAR␥, to circumvent the clinically observed side effects of full PPAR␥ agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPAR␥. Compared with full PPAR␥-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).adiponectin ͉ diabetes ͉ partial agonist ͉ PPAR pan-agonist ͉ Scaffold-based drug discovery T herapeutic approaches to Type 2 diabetes mellitus (T2DM), which currently affects Ϸ6% of adults in the United States (US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA; 2005), are generally polypharmaceutical in nature, targeting effects on insulin sensitivity and elements of the coincident dyslipidemia and cardiovascular diseases (1). However, polypharmacy in these treatment regimens has been cited as a potential additional risk factor (2), with many patients on 4 or more concomitant medications. A more effective strategy would be to use a single agent that possesses combined benefits from simultaneous inhibition or stimulation of several related targets, without the risks associated with combination therapy. However, optimizing activities against several targets is a complex design problem that necessitates judicious choice of targets and requires new ways in which therapeutic agents are generated.Two classes of marketed therapeutics, the fibrates (as lipidlowering agents) and the glitazones (as insulin-sensitizing drugs) target related receptors known as PPAR␣ and PPAR␥, respectively, whereas a third member of the subfamily, PPAR␦, has been the target of intense preclinical interest as an avenue for treatment of dyslipidemia (3). A pan-agonist, capable of stimulating the 3 peroxisome proliferator-activated receptors (PPARs) as a group, would be expected to be particularly useful in the treatment of T2DM from the standpoints of both efficacy and reduction in the additional risk factors associated with polypharmacy. Despite the close structural relationship between these 3 receptors, the search for compounds whi...

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“…Instead, partial-agonists display hydrophobic interaction in branch II or III, leading to the stabilization of H3 and the b-sheet region rather than H12. 38 A hydrogen bond with Ser342 at the border of two branches is observed for some partial agonists to reinforce this hydrophobic interaction. This H12-independent activation mechanism is characteristic of partial agonists.…”

Section: Mechanism Of Ppar Gamma Activation By Telmisartanmentioning

confidence: 93%

“…These include multiple intermolecular hydrogen bonds between carboxylic acid, or its bioisostere, and amino-acid residues Ser289, His323, His449 and Tyr473, as well as intramolecular hydrogen bonds among these four residues and Tyr327. 38 In addition, a certain level of occupation in branches II or III is required to increase affinity.…”

Section: Mechanism Of Ppar Gamma Activation By Telmisartanmentioning

confidence: 99%

Structural basis for telmisartan-mediated partial activation of PPAR gamma

et al. 2012

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Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as a partial agonist for peroxisome proliferator-activated receptor gamma (PPARc). To understand how telmisartan partially activates PPARc, we determined the ternary complex structure of PPARc, telmisartan, and a coactivator peptide from steroid receptor coactivator-1 at a resolution of 2.18 Å . Crystallographic analysis revealed that telmisartan exhibits an unexpected binding mode in which the central benzimidazole ring is engaged in a non-canonical-and suboptimal-hydrogen-bonding network around helix 12 (H12). This network differs greatly from that observed when full-agonists bind with PPARc and prompt high-coactivator recruitment through H12 stabilized by multiple hydrogen bonds. Binding with telmisartan results in a less stable H12 that in turn leads to attenuated coactivator binding, thus explaining the mechanism of partial activation.

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Partial Agonists Activate PPARγ Using a Helix 12 Independent Mechanism

Cited by 350 publications

References 49 publications

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Structural basis for telmisartan-mediated partial activation of PPAR gamma

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