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3fs1

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Revision as of 08:09, 2 March 2022

Crystal structure of HNF4a LBD in complex with the ligand and the coactivator PGC-1a fragment

Structural highlights

3fs1 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.
Ligands:
Related:	1pzl
Gene:	HNF4, HNF4A, NR2A1, TCF14 (HUMAN), PGC-1a (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

Publication Abstract from PubMed

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4alpha interacts, peroxisome proliferation-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1alpha recruitment, we have determined the crystal structure of HNF4alpha in complex with a fragment of PGC-1alpha containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4alpha toward the LXXLL motifs of PGC-1alpha could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.

Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation.,Rha GB, Wu G, Shoelson SE, Chi YI J Biol Chem. 2009 Dec 11;284(50):35165-76. Epub 2009 Oct 21. PMID:19846556^[4]

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

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
↑ Rha GB, Wu G, Shoelson SE, Chi YI. Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation. J Biol Chem. 2009 Dec 11;284(50):35165-76. Epub 2009 Oct 21. PMID:19846556 doi:10.1074/jbc.M109.052506

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3fs1"

@@ Line 1: / Line 1: @@
 ==Crystal structure of HNF4a LBD in complex with the ligand and the coactivator PGC-1a fragment==
-<StructureSection load='3fs1' size='340' side='right' caption='[[3fs1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+<StructureSection load='3fs1' size='340' side='right'caption='[[3fs1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3fs1]] 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=3FS1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FS1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3fs1]] 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=3FS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FS1 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene></td></tr>
+</td></tr><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>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1pzl|1pzl]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1pzl|1pzl]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HNF4, HNF4A, NR2A1, TCF14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PGC-1a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HNF4, HNF4A, NR2A1, TCF14 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PGC-1a ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3fs1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fs1 OCA], [http://pdbe.org/3fs1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fs1 RCSB], [http://www.ebi.ac.uk/pdbsum/3fs1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fs1 ProSAT]</span></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=3fs1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fs1 OCA], [https://pdbe.org/3fs1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fs1 RCSB], [https://www.ebi.ac.uk/pdbsum/3fs1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fs1 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://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:[http://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>
+[[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 ==
-[[http://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.
+[[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]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fs/3fs1_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fs/3fs1_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 37: / Line 37: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Chi, Y]]
 [[Category: Rha, G]]

3fs1

From Proteopedia

Revision as of 08:09, 2 March 2022

Crystal structure of HNF4a LBD in complex with the ligand and the coactivator PGC-1a fragment

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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