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PDBsum entry 3f1n

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protein ligands Protein-protein interface(s) links
Transcription PDB id
3f1n
Jmol
Contents
Protein chains
108 a.a. *
112 a.a. *
Ligands
EDO ×3
Waters ×180
* Residue conservation analysis
PDB id:
3f1n
Name: Transcription
Title: Crystal structure of a high affinity heterodimer of hif2 alpha and arnt c-terminal pas domains, with internally bound ethylene glycol.
Structure: Endothelial pas domain-containing protein 1. Chain: a. Fragment: hif2 alpha c-terminal pas domain. Synonym: epas-1, member of pas protein 2, basic-helix-loop- helix-pas protein mop2, hypoxia-inducible factor 2 alpha, hif-2 alpha, hif2 alpha, hif-1 alpha-like factor, hlf. Engineered: yes. Mutation: yes. Aryl hydrocarbon receptor nuclear translocator.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: epas1, hif2a, hypoxia-inducible factor 2 alpha, mop2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: arnt, aryl hydrocarbon receptor nuclear translocator.
Resolution:
1.48Å     R-factor:   0.173     R-free:   0.199
Authors: T.H.Scheuermann,D.R.Tomchick,M.Machius,Y.Guo,R.K.Bruick, K.H.Gardner
Key ref:
T.H.Scheuermann et al. (2009). Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A, 106, 450-455. PubMed id: 19129502 DOI: 10.1073/pnas.0808092106
Date:
28-Oct-08     Release date:   20-Jan-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q99814  (EPAS1_HUMAN) -  Endothelial PAS domain-containing protein 1
Seq:
Struc:
 
Seq:
Struc:
870 a.a.
108 a.a.*
Protein chain
Pfam   ArchSchema ?
P27540  (ARNT_HUMAN) -  Aryl hydrocarbon receptor nuclear translocator
Seq:
Struc:
 
Seq:
Struc:
789 a.a.
112 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     signal transduction   1 term 
  Biochemical function     signal transducer activity     1 term  

 

 
DOI no: 10.1073/pnas.0808092106 Proc Natl Acad Sci U S A 106:450-455 (2009)
PubMed id: 19129502  
 
 
Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor.
T.H.Scheuermann, D.R.Tomchick, M.Machius, Y.Guo, R.K.Bruick, K.H.Gardner.
 
  ABSTRACT  
 
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 HIF2alpha and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2alpha PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2alpha PAS-B modulates the affinity of the HIF2alpha: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.
 
  Selected figure(s)  
 
Figure 1.
Structural features of the HIF2 PAS-B* heterodimer. (A) Crystal structure of the high-affinity HIF2α PAS-B* (green) and ARNT PAS-B* (blue) heterodimer, including side chains that stabilize the heterodimer of PAS-B* proteins (sticks) and internally bound H[2]O molecules (red spheres). (B) The location of 8 ordered, internally bound water molecules (red mesh, F[o] − F[c] omit map contoured at 4.0 σ), within the HIF2α PAS-B* cavity (gray transparent surface). The red asterisk (*) denotes the location of the protease-accessible R330 residue.
Figure 3.
Structure of THS-044 in complex with HIF2α PAS-B*. THS-044 (gray sticks) occupies the apo-HIF2α PAS-B* internal cavity (transparent gray surface). The HIF2α PAS-B* HI loop in this structure was not modeled (dashed lines). For clarity, ARNT PAS-B* is not displayed.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21512126 C.L.Partch, and K.H.Gardner (2011).
Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B.
  Proc Natl Acad Sci U S A, 108, 7739-7744.  
21245039 N.Hao, M.L.Whitelaw, K.E.Shearwin, I.B.Dodd, and A.Chapman-Smith (2011).
Identification of residues in the N-terminal PAS domains important for dimerization of Arnt and AhR.
  Nucleic Acids Res, 39, 3695-3709.  
20395165 A.N.Koehler (2010).
A complex task? Direct modulation of transcription factors with small molecules.
  Curr Opin Chem Biol, 14, 331-340.  
20148691 B.E.McIntosh, J.B.Hogenesch, and C.A.Bradfield (2010).
Mammalian Per-Arnt-Sim proteins in environmental adaptation.
  Annu Rev Physiol, 72, 625-645.  
  20112293 C.L.Partch, and K.H.Gardner (2010).
Coactivator recruitment: a new role for PAS domains in transcriptional regulation by the bHLH-PAS family.
  J Cell Physiol, 223, 553-557.  
  20205712 C.Wotzlaw, S.Gneuss, R.Konietzny, and J.Fandrey (2010).
Nanoscopy of the cellular response to hypoxia by means of fluorescence resonance energy transfer (FRET) and new FRET software.
  PMC Biophys, 3, 5.  
19906177 P.Slavny, R.Little, P.Salinas, T.A.Clarke, and R.Dixon (2010).
Quaternary structure changes in a second Per-Arnt-Sim domain mediate intramolecular redox signal relay in the NifL regulatory protein.
  Mol Microbiol, 75, 61-75.  
19836329 A.Möglich, R.A.Ayers, and K.Moffat (2009).
Structure and signaling mechanism of Per-ARNT-Sim domains.
  Structure, 17, 1282-1294.  
19456125 A.Pandini, A.A.Soshilov, Y.Song, J.Zhao, L.Bonati, and M.S.Denison (2009).
Detection of the TCDD binding-fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis.
  Biochemistry, 48, 5972-5983.  
19324882 C.L.Partch, P.B.Card, C.A.Amezcua, and K.H.Gardner (2009).
Molecular basis of coiled coil coactivator recruitment by the aryl hydrocarbon receptor nuclear translocator (ARNT).
  J Biol Chem, 284, 15184-15192.  
19950993 J.Key, T.H.Scheuermann, P.C.Anderson, V.Daggett, and K.H.Gardner (2009).
Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B.
  J Am Chem Soc, 131, 17647-17654.
PDB codes: 3h7w 3h82
19805192 K.Lee, H.Zhang, D.Z.Qian, S.Rey, J.O.Liu, and G.L.Semenza (2009).
Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization.
  Proc Natl Acad Sci U S A, 106, 17910-17915.  
19487700 M.L.Privalsky, S.Lee, J.B.Hahm, B.M.Young, R.N.Fong, and I.H.Chan (2009).
The p160 coactivator PAS-B motif stabilizes nuclear receptor binding and contributes to isoform-specific regulation by thyroid hormone receptors.
  J Biol Chem, 284, 19554-19563.  
19722642 M.R.Evans, and K.H.Gardner (2009).
Slow transition between two beta-strand registers is dictated by protein unfolding.
  J Am Chem Soc, 131, 11306-11307.  
19196990 M.R.Evans, P.B.Card, and K.H.Gardner (2009).
ARNT PAS-B has a fragile native state structure with an alternative beta-sheet register nearby in sequence space.
  Proc Natl Acad Sci U S A, 106, 2617-2622.
PDB code: 2k7s
19845609 R.Konietzny, A.König, C.Wotzlaw, A.Bernadini, U.Berchner-Pfannschmidt, and J.Fandrey (2009).
Molecular imaging: into in vivo interaction of HIF-1alpha and HIF-2alpha with ARNT.
  Ann N Y Acad Sci, 1177, 74-81.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.