3h82

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains with the artificial ligand THS020

Structural highlights

3h82 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.5Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ARNT_HUMAN Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors responsible for the metazoan hypoxia response and promote tumor growth, metastasis, and resistance to cancer treatment. The C-terminal Per-ARNT-Sim (PAS) domain of HIF2alpha (HIF2alpha PAS-B) contains a preformed solvent-inaccessible cavity that binds artificial ligands that allosterically perturb the formation of the HIF heterodimer. To better understand how small molecules bind within this domain, we examined the structures and equilibrium and transition-state thermodynamics of HIF2alpha PAS-B with several artificial ligands using isothermal titration calorimetry, NMR exchange spectroscopy, and X-ray crystallography. Rapid association rates reveal that ligand binding is not dependent upon a slow conformational change in the protein to permit ligand access, despite the closed conformation observed in the NMR and crystal structures. Compensating enthalpic and entropic contributions to the thermodynamic barrier for ligand binding suggest a binding-competent transition state characterized by increased structural disorder. Finally, molecular dynamics simulations reveal conversion between open and closed conformations of the protein and pathways of ligand entry into the binding pocket.

Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B.,Key J, Scheuermann TH, Anderson PC, Daggett V, Gardner KH J Am Chem Soc. 2009 Dec 9;131(48):17647-54. PMID:19950993^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Key J, Scheuermann TH, Anderson PC, Daggett V, Gardner KH. Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B. J Am Chem Soc. 2009 Dec 9;131(48):17647-54. PMID:19950993 doi:10.1021/ja9073062

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3h82"

@@ Line 3: / Line 3: @@
 <StructureSection load='3h82' size='340' side='right'caption='[[3h82]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3h82]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H82 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H82 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3h82]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H82 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H82 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=020:N-(FURAN-2-YLMETHYL)-2-NITRO-4-(TRIFLUOROMETHYL)ANILINE'>020</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3f1p|3f1p]], [[3f1n|3f1n]], [[3f1o|3f1o]], [[2a24|2a24]], [[2b02|2b02]], [[1p97|1p97]], [[1x0o|1x0o]], [[3h7w|3h7w]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=020:N-(FURAN-2-YLMETHYL)-2-NITRO-4-(TRIFLUOROMETHYL)ANILINE'>020</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARNT, Aryl Hydrocarbon Receptor Nuclear Translocator, BHLHE2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EPAS1, HIF2A, Hypoxia Inducible Factor 2 alpha, MOP2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3h82 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h82 OCA], [https://pdbe.org/3h82 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h82 RCSB], [https://www.ebi.ac.uk/pdbsum/3h82 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h82 ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[https://www.uniprot.org/uniprot/EPAS1_HUMAN EPAS1_HUMAN]] Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:[https://omim.org/entry/611783 611783]]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.<ref>PMID:19208626</ref> <ref>PMID:18378852</ref> <ref>PMID:18184961</ref> <ref>PMID:22367913</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/ARNT_HUMAN ARNT_HUMAN]] Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia. [[https://www.uniprot.org/uniprot/EPAS1_HUMAN EPAS1_HUMAN]] Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD.
+[https://www.uniprot.org/uniprot/ARNT_HUMAN ARNT_HUMAN] Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 40: / Line 37: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Anderson, P C]]
+[[Category: Anderson PC]]
-[[Category: Daggett, V]]
+[[Category: Daggett V]]
-[[Category: Gardner, K H]]
+[[Category: Gardner KH]]
-[[Category: Key, J M]]
+[[Category: Key JM]]
-[[Category: Scheuermann, T H]]
+[[Category: Scheuermann TH]]
-[[Category: Activator]]
-[[Category: Alternative splicing]]
-[[Category: Angiogenesis]]
-[[Category: Congenital erythrocytosis]]
-[[Category: Developmental protein]]
-[[Category: Differentiation]]
-[[Category: Disease mutation]]
-[[Category: Dna-binding]]
-[[Category: Heterodimer]]
-[[Category: Hydroxylation]]
-[[Category: Nucleus]]
-[[Category: Pas domain]]
-[[Category: Phosphoprotein]]
-[[Category: Polymorphism]]
-[[Category: Protein ligand complex]]
-[[Category: Transcription]]
-[[Category: Transcription regulation]]
-[[Category: Ubl conjugation]]

3h82

From Proteopedia

Current revision

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains with the artificial ligand THS020

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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