Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor

被引:232
作者
Scheuermann, Thomas H. [1 ,2 ]
Tomchick, Diana R. [1 ]
Machius, Mischa [1 ]
Guo, Yan [1 ]
Bruick, Richard K. [1 ]
Gardner, Kevin H. [1 ,2 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
基金
美国国家卫生研究院;
关键词
internal cavity; NMR; X-ray crystallography; hypoxia; protein-ligand interactions; ARYL-HYDROCARBON RECEPTOR; STRUCTURAL BASIS; CRYSTAL-STRUCTURE; PROTEIN; OXYGEN; DIMERIZATION; FAMILY; ALPHA; NMR; HETERODIMERIZATION;
D O I
10.1073/pnas.0808092106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The hypoxia-inducible factor (HIF) basic helix-loop-helix Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (bHLH-PAS) transcription factors are master regulators of the conserved molecular mechanism by which metazoans sense and respond to reductions in local oxygen concentrations. In humans, HIF is critically important for the sustained growth and metastasis of solid tumors. Here, we describe crystal structures of the heterodimer formed by the C-terminal PAS domains from the HIF2 alpha and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2 alpha PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2 alpha PAS-B modulates the affinity of the HIF2 alpha:ARNT PAS-B heterodimer in vitro. Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings.
引用
收藏
页码:450 / 455
页数:6
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