2vqj: Difference between revisions
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< | ==Structure of HDAC4 catalytic domain bound to a trifluoromethylketone inhbitor== | ||
<StructureSection load='2vqj' size='340' side='right'caption='[[2vqj]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vqj]] is a 1 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=2VQJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VQJ FirstGlance]. <br> | |||
</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> | |||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DIO:1,4-DIETHYLENE+DIOXIDE'>DIO</scene>, <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'>[https://proteopedia.org/fgij/fg.htm?mol=2vqj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vqj OCA], [https://pdbe.org/2vqj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vqj RCSB], [https://www.ebi.ac.uk/pdbsum/2vqj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vqj ProSAT]</span></td></tr> | |||
</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 == | |||
[[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/vq/2vqj_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</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=2vqj ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:18614528</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2vqj" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
== | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Bottomley | [[Category: Bottomley MJ]] | ||
[[Category: Carfi | [[Category: Carfi A]] | ||
[[Category: Cirillo | [[Category: Cirillo A]] | ||
[[Category: De Francesco R]] | |||
[[Category: Francesco | [[Category: Di Giovine P]] | ||
[[Category: | [[Category: Ferrigno F]] | ||
[[Category: | [[Category: Gallinari P]] | ||
[[Category: | [[Category: Jones P]] | ||
[[Category: | [[Category: Lo Surdo P]] | ||
[[Category: Neddermann P]] | |||
[[Category: Scarpelli R]] | |||
[[Category: Surdo | [[Category: Steinkuhler C]] | ||
[[Category: | |||
[[Category: | |||
[[Category: | |||
Latest revision as of 12:32, 6 November 2024
Structure of HDAC4 catalytic domain bound to a trifluoromethylketone inhbitorStructure of HDAC4 catalytic domain bound to a trifluoromethylketone inhbitor
Structural highlights
DiseaseHDAC4_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] FunctionHDAC4_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 PubMedHistone 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 AlsoReferences
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