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4h6j

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Revision as of 19:59, 24 January 2018

Identification of Cys 255 in HIF-1 as a novel site for development of covalent inhibitors of HIF-1 /ARNT PasB domain protein-protein interaction.

Structural highlights

4h6j is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	3f1p
Gene:	HIF-1 alpha (HUMAN), ARNT (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HIF1A_HUMAN] Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] [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.

Publication Abstract from PubMed

The heterodimer HIF-1alpha (hypoxia inducible factor)/HIF-beta (also known as ARNT-aryl hydrocarbon nuclear translocator) is a key mediator of cellular response to hypoxia. The interaction between these monomer units can be modified by the action of small molecules in the binding interface between their C-terminal heterodimerization (PasB) domains. Taking advantage of the presence of several cysteine residues located in the allosteric cavity of HIF-1alpha PasB domain, we applied a cysteine-based reactomics "hotspot identification" strategy to locate regions of HIF-1alpha PasB domain critical for its interaction with ARNT. COMPOUND 5 was identified using a mass spectrometry-based primary screening strategy and was shown to react specifically with Cys255 of the HIF-1alpha PasB domain. Biophysical characterization of the interaction between PasB domains of HIF-1alpha and ARNT revealed that covalent binding of COMPOUND 5 to Cys255 reduced binding affinity between HIF-1alpha and ARNT PasB domains approximately 10-fold. Detailed NMR structural analysis of HIF-1alpha-PasB-COMPOUND 5 conjugate showed significant local conformation changes in the HIF-1alpha associated with key residues involved in the HIF-1alpha/ARNT PasB domain interaction as revealed by the crystal structure of the HIF-1alpha/ARNT PasB heterodimer. Our screening strategy could be applied to other targets to identify pockets surrounding reactive cysteines suitable for development of small molecule modulators of protein function.

Identification of Cys255 in HIF-1alpha as a novel site for development of covalent inhibitors of HIF-1alpha/ARNT PasB domain protein-protein interaction.,Cardoso R, Love R, Nilsson CL, Bergqvist S, Nowlin D, Yan J, Liu KK, Zhu J, Chen P, Deng YL, Dyson HJ, Greig MJ, Brooun A Protein Sci. 2012 Dec;21(12):1885-96. doi: 10.1002/pro.2172. Epub 2012 Nov 9. PMID:23033253^[10]

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

References

↑ Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 1999 Jan 1;13(1):64-75. PMID:9887100
↑ Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001 Sep 17;20(18):5197-206. PMID:11566883 doi:10.1093/emboj/20.18.5197
↑ Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001 Apr 20;292(5516):468-72. Epub 2001 Apr 5. PMID:11292861 doi:10.1126/science.1059796
↑ Bae SH, Jeong JW, Park JA, Kim SH, Bae MK, Choi SJ, Kim KW. Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun. 2004 Nov 5;324(1):394-400. PMID:15465032 doi:10.1016/j.bbrc.2004.09.068
↑ Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y, Fang J, Caro J, Sang N. Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha. J Biol Chem. 2006 May 12;281(19):13612-9. Epub 2006 Mar 15. PMID:16543236 doi:M600456200
↑ Choi SM, Choi KO, Park YK, Cho H, Yang EG, Park H. Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells. J Biol Chem. 2006 Nov 10;281(45):34056-63. Epub 2006 Sep 13. PMID:16973622 doi:M603913200
↑ Berta MA, Mazure N, Hattab M, Pouyssegur J, Brahimi-Horn MC. SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity. Biochem Biophys Res Commun. 2007 Aug 31;360(3):646-52. Epub 2007 Jun 27. PMID:17610843 doi:10.1016/j.bbrc.2007.06.103
↑ Li Y, Lim S, Hoffman D, Aspenstrom P, Federoff HJ, Rempe DA. HUMMR, a hypoxia- and HIF-1alpha-inducible protein, alters mitochondrial distribution and transport. J Cell Biol. 2009 Jun 15;185(6):1065-81. doi: 10.1083/jcb.200811033. PMID:19528298 doi:10.1083/jcb.200811033
↑ Gimm T, Wiese M, Teschemacher B, Deggerich A, Schodel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Honing S, Eckardt KU, Warnecke C. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 2010 Nov;24(11):4443-58. doi: 10.1096/fj.10-159806. Epub 2010 Jul 12. PMID:20624928 doi:10.1096/fj.10-159806
↑ Cardoso R, Love R, Nilsson CL, Bergqvist S, Nowlin D, Yan J, Liu KK, Zhu J, Chen P, Deng YL, Dyson HJ, Greig MJ, Brooun A. Identification of Cys255 in HIF-1alpha as a novel site for development of covalent inhibitors of HIF-1alpha/ARNT PasB domain protein-protein interaction. Protein Sci. 2012 Dec;21(12):1885-96. doi: 10.1002/pro.2172. Epub 2012 Nov 9. PMID:23033253 doi:10.1002/pro.2172

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4h6j"

@@ Line 1: / Line 1: @@
 ==Identification of Cys 255 in HIF-1 as a novel site for development of covalent inhibitors of HIF-1 /ARNT PasB domain protein-protein interaction.==
 <StructureSection load='4h6j' size='340' side='right' caption='[[4h6j]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4h6j]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4H6J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H6J FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4h6j]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4H6J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H6J FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3f1p|3f1p]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HIF-1 alpha ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), ARNT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HIF-1 alpha ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ARNT ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4h6j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h6j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h6j RCSB], [http://www.ebi.ac.uk/pdbsum/4h6j PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4h6j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h6j OCA], [http://pdbe.org/4h6j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4h6j RCSB], [http://www.ebi.ac.uk/pdbsum/4h6j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4h6j ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4h6j" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Factor inhibiting HIF|Factor inhibiting HIF]]
-*[[Hypoxia-inducible factor prolyl hydroxylase|Hypoxia-inducible factor prolyl hydroxylase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Bergqvist, S]]
 [[Category: Brooun, A]]

4h6j

From Proteopedia

Revision as of 19:59, 24 January 2018

Identification of Cys 255 in HIF-1 as a novel site for development of covalent inhibitors of HIF-1 /ARNT PasB domain protein-protein interaction.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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