Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor

Estébanez‐Perpiñá, Eva; Arnold, Leggy A.; Jouravel, Natalia; Togashi, Marie; Blethrow, Justin D.; Mar, Ellena; Nguyen, Phuong; Phillips, Kevin J.; Baxter, John D.; Webb, Paul; Guy, R. Kiplin; Fletterick, Robert J.

doi:10.1210/me.2007-0174

Cited by 56 publications

(61 citation statements)

References 35 publications

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“…Point mutation could also shift equilibrium between different oligomeric states in Pyrococcus furiosus mutants (1iz5-1iz4) and disrupt the salt bridge stabilizing the functional dimer in nuclear hormone receptors (2pin-1n46). All these findings were supported by experimental studies (32)(33)(34). Other mechanisms observed in our set of dimers and monomers included:-presence of common stabilizing ligands on interfaces including ions ("ligand induced dimerization");-regulation of dimerization through posttranslational modifications including phosphorylation and disulfide bond formation between two subunits; and -presence of insertions/deletions which favored dimeric or monomeric states.…”

Section: Resultssupporting

confidence: 79%

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

Hashimoto

Panchenko

2010

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

171

147

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The main principles of protein-protein recognition are elucidated by the studies of homooligomers which in turn mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell-cell adhesion processes. Here we explore oligomeric states of homologous proteins in various organisms to better understand the functional roles and evolutionary mechanisms of homooligomerization. We observe a great diversity in mechanisms controlling oligomerization and focus in our study on insertions and deletions in homologous proteins and how they enable or disable complex formation. We show that insertions and deletions which differentiate monomers and dimers have a significant tendency to be located on the interaction interfaces and about a quarter of all proteins studied and forty percent of enzymes have regions which mediate or disrupt the formation of oligomers. We suggest that relatively small insertions or deletions may have a profound effect on complex stability and/or specificity. Indeed removal of complex enabling regions from protein structures in many cases resulted in the complete or partial loss of stability. Moreover, we find that insertions and deletions modulating oligomerization have a lower aggregation propensity and contain a larger fraction of polar, charged residues, glycine and proline compared to conventional interfaces and protein surface. Most likely, these regions may mediate specific interactions, prevent nonspecific dysfunctional aggregation and preclude undesired interactions between close paralogs therefore separating their functional pathways. Last, we show how the presence or absence of insertions and deletions on interfaces might be of practical value in annotating protein oligomeric states.homodimer | homooligomer protein | protein structural evolution

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Section: Resultssupporting

confidence: 79%

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

Hashimoto

Panchenko

2010

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

171

147

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“…compound (23) showed slightly increased activity compared with the unsubstituted form (22). The SAR analysis suggested that sterically hindered amides give more favorable interactions with TR␤, which is consistent with the presence of two deep hydrophobic pockets in the targeted binding site (33).…”

Section: Resultssupporting

confidence: 54%

“…These time-dependent, irreversible inhibitors work by generating an enone in situ followed by a reaction between the electrophilic enone and a nucleophilic cysteine in the coactivator binding pocket. The x-ray structure of a ␤-aminoketonederived enone bound to TR␤ supports this hypothesis (33). TR␤ is unique among the nuclear receptors in having four cysteine residues (Cys-294, Cys-298, Cys-308, and Cys-309) located in or near the coactivator binding site.…”

mentioning

confidence: 74%

“…Two independent experiments were carried out in triplicate out for each compound. ␤-Aminoketone SJ-1 ([3-dibutylamino]-1-(4-hexylphenyl)propan-1-one (DHPPA)), a known thyroid hormone receptor antagonist (33), was used as a positive control. For fluorescence polarization assays using other NRs, see supplemental materials.…”

Section: Methodsmentioning

confidence: 99%

“…The ␤-aminoketone inhibitor series blocks TR␤-SRC2 interaction by irreversibly binding to the activator interaction domain via covalent coupling with Cys-298 (30,33). The knowledge of this mechanism of TR␤ inhibition and the similarity of the MSNB series to the GW series of irreversible PPAR␦ ligand antagonists led us to test whether the MSNB series were irreversible inhibitors as well.…”

Section: Mechanism Of Inhibition By Msnb Analogs-mentioning

confidence: 99%

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Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Hwang

Huang

Arnold

et al. 2011

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TR␤ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T 3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPAR␥ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TR␤ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TR␤ to disrupt SRC2 association.

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Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors

Caboni

Lloyd

2012

Med. Res. Rev.

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Nuclear receptors (NRs) are a family of ligand-modulated transcription factors with significant therapeutic relevance from metabolic disorders and inflammation to cancer, neurodegenerative, and psychiatric disorders. Drug discovery efforts are typically concentrated on modulating the natural ligand action within the ligand-binding pocket (LBP) in the C-terminal ligand-binding domain (LBD). Drawbacks of LBP-based strategies include physiological alterations due to disruption of ligand binding and difficulties in achieving tissue specificity. Furthermore, the lack of a "pure" and predictable mechanism of action predisposes such intervention toward drug resistance. Recent outstanding progress in our understanding of NR biology has shifted the focus of drug discovery efforts from inside to outside the LBP, affording consideration to the interaction between NRs and coactivator proteins, the interaction between NRs and DNA and the NRs' ligand-independent functions. This review encompasses such currently available NR non-LBP-based interventions and their potential application in therapy or as specific tools to probe NR biology.

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Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor

Cited by 56 publications

References 35 publications

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors

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