Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

Boerma, LeeAnn J.; Xia, Gang; Qui, Cheng; Cox, Bryan; Chalmers, Michael J.; Smith, Craig D.; Lobo-Ruppert, Susan M.; Griffin, Patrick R.; Muccio, Donald D.; Renfrow, Matthew B.

doi:10.1074/jbc.m113.476861

Cited by 50 publications

(109 citation statements)

References 62 publications

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“…1, 2, 10 Here crystal strutures of hRXRα-LBD homodimers containing the coactivator peptide GRIP-1 with one of four potent agonists ( 6 , 9, 10 and 11 ) were obtained and compared. Crystals of the homodimer containing the partial agonists, 8 or 12 , were not successfully obtained after repeated tries using similar conditions of crystallization to those of full agonists.…”

Section: Resultsmentioning

confidence: 99%

“…Each rexinoid adopts an L-shaped conformation, which is characteristic of the way rexinoid agonists or the pan-agonist 9-cis-retinoic acid bind to the receptor. 1, 2 The binding of the rexinoid agonists cause similar, but not identical, conformational and dynamical changes to the ligand binding domain enabling the recruitment of an amphipathic coactivator peptide containing the LL xx LL motif. Each rexinoid reduces proliferation and enhances apoptosis in mammary tumors, and efficiently prevents mammary cancers in rodent models.…”

Section: Introductionmentioning

confidence: 99%

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Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers

et al. 2015

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(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a di-substituted cyclohexenyl ring. Among the twelve Class I and Class II rexinoids evaluated, the Class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers

et al. 2015

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“…19 The rate of hydrogen/deuterium exchange of backbone amide hydrogens reflects the conformational mobility, hydrogen bonding strength, and solvent accessibility in the protein structure. 20 In fact, the in-solution 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 dynamics of several NRs, including VDR, have been investigated using HDX-MS. [23][24][25][26][27][28][29][30][31][32][33] To develop strong antagonists and to reveal the mechanism of active antagonism of the VDR, we designed and synthesized vitamin D analogues with bulky substituents at the side chain terminus and used them to probe changes in the VDR-LBD structure upon binding to synthetic active antagonists. Here, we report the synthesis and biological evaluation of compounds 2a,b-6a,b ( Figure 1) and the results of static X-ray crystallographic and dynamic HDX-MS analyses of the VDR-LBD/antagonist complex.…”

Section: Introductionmentioning

confidence: 99%

Helix12-Stabilization Antagonist of Vitamin D Receptor

et al. 2016

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To develop strong vitamin D receptor (VDR) antagonists and reveal their antagonistic mechanism, we designed and synthesized vitamin D analogues with bulky side chains based on the "active antagonist" concept in which antagonist prevents helix 12 (H12) folding. Of the synthesized analogues, compounds 3a and 3b showed strong antagonistic activity. Dynamic hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) and static X-ray crystal structure analyses indicated that compound 3a stabilizes H11-H12 but displaces H6-H7 so that 3a is a novel rather than "active" or "passive" type of antagonist. We classified 3a as a third type of antagonist and called it "H11-H12 stabilization antagonist". HDX-MS analysis indicated that antagonist 3b is an "active" antagonist. To date there are no reports relating to nuclear receptor antagonist that strongly stabilizes H12. In this study, we found first VDR antagonist that stabilizes H12 and we showed that antagonistic mechanism is diverse depending on each antagonist structure. Additionally, HDX-MS was proven to be very useful for investigations of protein structure alterations resulting from ligand binding.

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“…In the X-ray crystal structure of hRXRα-LBD homodimers bound to 9cUAB30 with the coactivator peptide GRIP-1, we revealed that the binding pocket contained enough space to accommodate a small lipophilic group on the tetralone ring. 10 Methyl substitution has proven to be very effective in improving activity through lipophilic interactions and/or from energetic gains realized by burial of the methyl group in the hydrophobic pockets of the protein. 11 Racemic 1 ((±)- 1 ) possesses a methyl group at the 4-position of the tetralone ring, and it is also known as 4-methyl-9c-UAB30 in the literature (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention

Desphande¹,

Xia²,

Boerma³

et al. 2014

Bioorganic & Medicinal Chemistry

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(2E,4E,6Z,8Z)-8-(3’,4’-Dihydro-1’(2H)-naphthalen-1’-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.

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Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

Cited by 50 publications

References 62 publications

Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers

Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers

Helix12-Stabilization Antagonist of Vitamin D Receptor

Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention

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