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| | <StructureSection load='2vqo' size='340' side='right'caption='[[2vqo]], [[Resolution|resolution]] 2.15Å' scene=''> | | <StructureSection load='2vqo' size='340' side='right'caption='[[2vqo]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vqo]] 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=2VQO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2VQO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vqo]] 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=2VQO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VQO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TFG:2,2,2-TRIFLUORO-1-{5-[(3-PHENYL-5,6-DIHYDROIMIDAZO[1,2-A]PYRAZIN-7(8H)-YL)CARBONYL]THIOPHEN-2-YL}ETHANE-1,1-DIOL'>TFG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.15Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vqw|2vqw]], [[2vqq|2vqq]], [[2vqv|2vqv]], [[2vqm|2vqm]], [[2vqj|2vqj]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TFG:2,2,2-TRIFLUORO-1-{5-[(3-PHENYL-5,6-DIHYDROIMIDAZO[1,2-A]PYRAZIN-7(8H)-YL)CARBONYL]THIOPHEN-2-YL}ETHANE-1,1-DIOL'>TFG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2vqo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vqo OCA], [http://pdbe.org/2vqo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vqo RCSB], [http://www.ebi.ac.uk/pdbsum/2vqo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2vqo 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=2vqo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vqo OCA], [https://pdbe.org/2vqo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vqo RCSB], [https://www.ebi.ac.uk/pdbsum/2vqo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vqo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[https://omim.org/entry/600430 600430]. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.<ref>PMID:20691407</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.<ref>PMID:10523670</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bottomley, M J]] | + | [[Category: Bottomley MJ]] |
| - | [[Category: Carfi, A]] | + | [[Category: Carfi A]] |
| - | [[Category: Cirillo, A]] | + | [[Category: Cirillo A]] |
| - | [[Category: Ferrigno, F]] | + | [[Category: De Francesco R]] |
| - | [[Category: Francesco, R De]]
| + | [[Category: Di Giovine P]] |
| - | [[Category: Gallinari, P]] | + | [[Category: Ferrigno F]] |
| - | [[Category: Giovine, P Di]] | + | [[Category: Gallinari P]] |
| - | [[Category: Jones, P]] | + | [[Category: Jones P]] |
| - | [[Category: Neddermann, P]] | + | [[Category: Lo Surdo P]] |
| - | [[Category: Scarpelli, R]] | + | [[Category: Neddermann P]] |
| - | [[Category: Steinkuhler, C]]
| + | [[Category: Scarpelli R]] |
| - | [[Category: Surdo, P Lo]]
| + | [[Category: Steinkuhler C]] |
| - | [[Category: Chromatin]] | + | |
| - | [[Category: Chromatin regulator]] | + | |
| - | [[Category: Coiled coil]] | + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Hdac]]
| + | |
| - | [[Category: Hdaci]]
| + | |
| - | [[Category: Histone deacetylase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Repressor]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[Category: Ubl conjugation]]
| + | |
| - | [[Category: Zinc]]
| + | |
| Structural highlights
Disease
HDAC4_HUMAN Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:600430. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.[1]
Function
HDAC4_HUMAN Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.[2]
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
Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.
Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.,Bottomley MJ, Lo Surdo P, Di Giovine P, Cirillo A, Scarpelli R, Ferrigno F, Jones P, Neddermann P, De Francesco R, Steinkuhler C, Gallinari P, Carfi A J Biol Chem. 2008 Sep 26;283(39):26694-704. Epub 2008 Jul 8. PMID:18614528[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, McLeod DR, Zondag S, Toriello HV, Magenis RE, Elsea SH. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010 Aug 13;87(2):219-28. doi: 10.1016/j.ajhg.2010.07.011. PMID:20691407 doi:10.1016/j.ajhg.2010.07.011
- ↑ Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th'ng J, Han J, Yang XJ. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol. 1999 Nov;19(11):7816-27. PMID:10523670
- ↑ Bottomley MJ, Lo Surdo P, Di Giovine P, Cirillo A, Scarpelli R, Ferrigno F, Jones P, Neddermann P, De Francesco R, Steinkuhler C, Gallinari P, Carfi A. Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J Biol Chem. 2008 Sep 26;283(39):26694-704. Epub 2008 Jul 8. PMID:18614528 doi:http://dx.doi.org/10.1074/jbc.M803514200
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