PDBsum entry 4zp4

Protein transport/transcription

PDB id: 4zp4

Contents

Protein chains

261 a.a.

295 a.a.

Waters ×139

PDB id:

4zp4

Name:

Protein transport/transcription

Title:

Crystal structure of the heterodimeric hif-2a:arnt complex

Structure:

Aryl hydrocarbon receptor nuclear translocator. Chain: a, c. Fragment: unp residues 82-464. Synonym: arnt protein, dioxin receptor, nuclear translocator, hypoxia-inducible factor 1-beta, hif1-beta. Engineered: yes. Endothelial pas domain-containing protein 1. Chain: b, d. Fragment: unp residues 3-361.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: arnt. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: epas1, hif2a.

Resolution:

2.36Å R-factor: 0.203 R-free: 0.232

Authors:

D.Wu,N.Potluri,J.Lu,Y.Kim,F.Rastinejad

Key ref:

D.Wu et al. (2015). Structural integration in hypoxia-inducible factors. Nature, 524, 303-308. PubMed id: 26245371 DOI: 10.1038/nature14883

Date:

07-May-15 Release date: 12-Aug-15

Protein chains

P53762  (ARNT_MOUSE) -  Aryl hydrocarbon receptor nuclear translocator from Mus musculus

Seq: 791 a.a.

Struc: 261 a.a.

Protein chains

P97481  (EPAS1_MOUSE) -  Endothelial PAS domain-containing protein 1 from Mus musculus

Seq: 874 a.a.

Struc: 295 a.a.

DOI no: 10.1038/nature14883

Nature 524:303-308 (2015)

PubMed id: 26245371

Structural integration in hypoxia-inducible factors.

D.Wu, N.Potluri, J.Lu, Y.Kim, F.Rastinejad.

ABSTRACT

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α-ARNT and HIF-1α-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α-ARNT and HIF-1α-ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.