Structural integration in hypoxia-inducible factors

Wu, Dalei; Potluri, Nalini; Lu, Jiayi; Kim, Young Chang; Rastinejad, Fraydoon

doi:10.1038/nature14883

Cited by 266 publications

(379 citation statements)

References 64 publications

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“…Although AHR and ARNT have similar domain structures (Fig. 1A), we observed that ARNT curls around the AHR into a highly intertwined asymmetric architecture, similar to those of the CLOCK-BMAL1 and the HIF-α-ARNT complexes (33,34). The bHLH and PAS-A domains of AHR and ARNT form extensive domain-domain and cross-domain interactions via highly conserved residues of AHR ( Fig.…”

Section: Quaternary Architecture Of Ahr-arnt Heterodimer Inmentioning

confidence: 89%

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Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

Seok

Lee²,

Li³

et al. 2017

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

106

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The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.he aryl hydrocarbon receptor (AHR) belongs to the PER-ARNT-SIM (PAS) family transcription factor that mediates broad responses to cellular and environmental cues. The AHR has been shown to be activated by diverse environmental toxicants and endogenous ligands, and play an important role in adaptive metabolism, dioxin toxicity, and normal vascular and immune development (1, 2), ever since it was identified four decades ago for mediating metabolic responses to aryl hydrocarbon toxicants (3, 4) and the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (5). The AHR was more recently found to mediate diverse cellular and physiological responses and likely respond to unknown endogenous AHR ligands (1, 2, 6-8). Developmentally, the AHR plays a role in the normal development and function of both the vascular and immune systems (9-12), and has close links to cancer, metabolic, immune, and cardiovascular diseases (13-18).Intense efforts in the past four decades have yielded important insights into the molecular processes governing AHR signaling. Newly synthesized AHR is located in cytosol and associated with the chaperones Hsp90 (19), P23 (20, 21), and AHR associated protein 9 (ARA9, also known as XAP2 or AIP) (22-24). Binding of ligands induces conformational changes in the AHR that lead to exposure of nuclear localization sequences (NLS) (25, 26). Following nuclear translocation, the AHR exchanges chaperones for a transcription partner, ARNT (1) and the AHR-ARNT heterodimer binds near the promoters of target genes at dioxin-response element (DRE...

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Section: Quaternary Architecture Of Ahr-arnt Heterodimer Inmentioning

confidence: 89%

“…1C). Although not visible in the structure, several loops of AHR and ARNT PAS-A domains bear positively charged residues, which could be oriented for interaction with the target DNA outside the DRE consensus sequence (34) (Fig. S3C).…”

Section: Specific Recognition Of Dre and Comparison With Hypoxia Respmentioning

confidence: 99%

Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

Seok

Lee²,

Li³

et al. 2017

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

106

View full text Add to dashboard Cite

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“…2A). The significance of these perturbations became apparent in light of a recently published crystal structure of the more complete HLH-A-B heterodimer of HIF2a and ARNT, which revealed an alternative spatial arrangement and interface of the two PAS-B domains (25). Although the folds for both HIF2a PAS-B domain structures are essentially identical, the domain arrangement of the HLH-A-B dimer revealed that the PT2385 perturbed amino acids are now located at the HIF2a/ARNT PAS-B interface (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Examination of the recently reported crystal structure of the more complete helix-loop-helix:PAS-A:PAS-B (HLH-A-B) heterodimer of HIF2a and ARNT reveals that the HIF2a/ARNT PAS-B Ã domains occupy a completely different spatial arrangement and dimer interface (25). In this orientation, the perturbed residues now reside at the HIF2a/ARNT PAS-B interface, suggesting that PT2385-induced changes to residues H293, M252, and Y278 are responsible for dimer disruption (Fig.…”

Section: Binding and Dimerization Disruptionmentioning

confidence: 99%

A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

et al. 2016

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More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1a and HIF2a, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2a that allosterically blocks its dimerization with the

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“…There are no known endogenous ligands for HIF-2α, but this cavity has been targeted for drug development and several promising highly specific smallmolecule inhibitors have been identified that efficaciously disrupt HIF-2α heterodimerization with ARNT and block DNA binding and transcription of target genes in cultured cells (141). These reagents coupled with recent HIF structural analysis provide a framework to specifically regulate HIF-1α and HIF-2α and will aid the development of clinical tools to alter protumor inflammatory responses or antitumor immune responses (142).…”

Section: Hif-based Therapeutics In Cancermentioning

confidence: 99%