Bidirectional modulation of HIF-2 activity through chemical ligands View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-04

AUTHORS

Dalei Wu, Xiaoyu Su, Jingping Lu, Sheng Li, Becky L. Hood, Stefan Vasile, Nalini Potluri, Xiaotong Diao, Youngchang Kim, Sepideh Khorasanizadeh, Fraydoon Rastinejad

ABSTRACT

Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2α subunit and its obligate partner subunit ARNT. Enhanced HIF-2 activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2α chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2α PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2α agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2α PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2α-ARNT heterodimerization. More... »

PAGES

367-376

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41589-019-0234-5

DOI

http://dx.doi.org/10.1038/s41589-019-0234-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112362627

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30804532


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Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

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N-Triples is a line-based linked data format ideal for batch operations.

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Turtle is a human-readable linked data format.

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RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/s41589-019-0234-5'


 

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