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| - | [[Image:1pzl.gif|left|200px]] | |
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| - | {{Structure
| + | ==Crystal structure of HNF4a LBD in complex with the ligand and the coactivator SRC-1 peptide== |
| - | |PDB= 1pzl |SIZE=350|CAPTION= <scene name='initialview01'>1pzl</scene>, resolution 2.1Å
| + | <StructureSection load='1pzl' size='340' side='right'caption='[[1pzl]], [[Resolution|resolution]] 2.10Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene>
| + | <table><tr><td colspan='2'>[[1pzl]] 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=1PZL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PZL FirstGlance]. <br> |
| - | |ACTIVITY=
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | |GENE= HNF4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene></td></tr> |
| - | |DOMAIN=
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1pzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pzl OCA], [https://pdbe.org/1pzl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pzl RCSB], [https://www.ebi.ac.uk/pdbsum/1pzl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pzl ProSAT]</span></td></tr> |
| - | |RELATEDENTRY=[[1m7w|1M7W]], [[1lv2|1LV2]]
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pzl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pzl OCA], [http://www.ebi.ac.uk/pdbsum/1pzl PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1pzl RCSB]</span> | + | == Disease == |
| - | }}
| + | [https://www.uniprot.org/uniprot/HNF4A_HUMAN HNF4A_HUMAN] Defects in HNF4A are the cause of maturity-onset diabetes of the young type 1 (MODY1) [MIM:[https://omim.org/entry/125850 125850]; also symbolized MODY-1. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:9313765</ref> <ref>PMID:9243109</ref> <ref>PMID:9449683</ref> |
| - | | + | == Function == |
| - | '''Crystal structure of HNF4a LBD in complex with the ligand and the coactivator SRC-1 peptide'''
| + | [https://www.uniprot.org/uniprot/HNF4A_HUMAN HNF4A_HUMAN] Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine. |
| - | | + | == Evolutionary Conservation == |
| - | | + | [[Image:Consurf_key_small.gif|200px|right]] |
| - | ==Overview== | + | Check<jmol> |
| - | In addition to suggesting that fatty acids are endogenous ligands, our recent crystal structure of HNF-4alpha showed an unusual degree of structural flexibility in the AF-2 domain (helix alpha12). Although every molecule contained a fatty acid within its ligand binding domain, one molecule in each homodimer was in an open inactive conformation with alpha12 fully extended and colinear with alpha10. By contrast, the second molecule in each homodimer was in a closed conformation with alpha12 folded against the body of the domain in what is widely considered to be the active state. This indicates that although ligand binding is necessary, it is not sufficient to induce an activating structural transition in HNF-4alpha as is commonly suggested to occur for nuclear receptors. To further assess potential mechanisms of activation, we have solved a structure of human HNF-4alpha bound to both fatty acid ligand and a coactivator sequence derived from SRC-1. The mode of coactivator binding is similar to that observed for other nuclear receptors, and in this case, all of the molecules adopt the closed active conformation. We conclude that for HNF-4alpha, coactivator rather than ligand binding locks the active conformation.
| + | <jmolCheckbox> |
| - | | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pz/1pzl_consurf.spt"</scriptWhenChecked> |
| - | ==Disease== | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| - | Known disease associated with this structure: MODY, type I OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600281 600281]], Diabetes mellitus, noninsulin-dependent OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600281 600281]]
| + | <text>to colour the structure by Evolutionary Conservation</text> |
| - | | + | </jmolCheckbox> |
| - | ==About this Structure== | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1pzl ConSurf]. |
| - | 1PZL is a [[Protein complex]] structure of sequences 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=1PZL OCA].
| + | <div style="clear:both"></div> |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | Structural basis for HNF-4alpha activation by ligand and coactivator binding., Duda K, Chi YI, Shoelson SE, J Biol Chem. 2004 May 28;279(22):23311-6. Epub 2004 Feb 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14982928 14982928]
| + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Chi, Y I.]] | + | [[Category: Chi Y-I]] |
| - | [[Category: Dhe-paganon, S.]] | + | [[Category: Dhe-paganon S]] |
| - | [[Category: Duda, K.]] | + | [[Category: Duda K]] |
| - | [[Category: Shoelson, S.]] | + | [[Category: Shoelson S]] |
| - | [[Category: transcription]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:06:46 2008''
| + | |
| Structural highlights
Disease
HNF4A_HUMAN Defects in HNF4A are the cause of maturity-onset diabetes of the young type 1 (MODY1) [MIM:125850; also symbolized MODY-1. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[1] [2] [3]
Function
HNF4A_HUMAN Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI. Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes. 1997 Oct;46(10):1652-7. PMID:9313765
- ↑ Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT. A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young. Diabetologia. 1997 Jul;40(7):859-62. PMID:9243109
- ↑ Hani EH, Suaud L, Boutin P, Chevre JC, Durand E, Philippi A, Demenais F, Vionnet N, Furuta H, Velho G, Bell GI, Laine B, Froguel P. A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest. 1998 Feb 1;101(3):521-6. PMID:9449683 doi:10.1172/JCI1403
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