3mu6: Difference between revisions
New page: '''Unreleased structure''' The entry 3mu6 is ON HOLD Authors: Jayathilaka, N., Han, A., Gaffney, K., Dey, R., He, J., Ye, J., Gao, T., Petasis, N. A., Chen, L. Description: Inhibiting ... |
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==Inhibiting the Binding of Class IIa Histone Deacetylases to Myocyte Enhancer Factor-2 by Small Molecules== | |||
<StructureSection load='3mu6' size='340' side='right'caption='[[3mu6]], [[Resolution|resolution]] 2.43Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mu6]] is a 8 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=3MU6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MU6 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]] 2.434Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BXL:(3E)-N~8~-(2-AMINOPHENYL)-N~1~-PHENYLOCT-3-ENEDIAMIDE'>BXL</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=3mu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mu6 OCA], [https://pdbe.org/3mu6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mu6 RCSB], [https://www.ebi.ac.uk/pdbsum/3mu6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mu6 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/MEF2A_HUMAN MEF2A_HUMAN] Defects in MEF2A are a cause of coronary artery disease, autosomal dominant, type 1 (ADCAD1) [MIM:[https://omim.org/entry/608320 608320]. A common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MEF2A_HUMAN MEF2A_HUMAN] Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific genes. Also involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. In cerebellar granule neurons, phosphorylated and sumoylated MEF2A represses transcription of NUR77 promoting synaptic differentiation.<ref>PMID:9858528</ref> <ref>PMID:11904443</ref> <ref>PMID:12691662</ref> <ref>PMID:15834131</ref> <ref>PMID:16563226</ref> <ref>PMID:16371476</ref> <ref>PMID:16484498</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA. We used X-ray crystallography and (19)F NMR to show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development. | |||
Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.,Jayathilaka N, Han A, Gaffney KJ, Dey R, Jarusiewicz JA, Noridomi K, Philips MA, Lei X, He J, Ye J, Gao T, Petasis NA, Chen L Nucleic Acids Res. 2012 Mar 6. PMID:22396528<ref>PMID:22396528</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3mu6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Myocyte enhancer factor 2|Myocyte enhancer factor 2]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chen L]] | |||
[[Category: Dey R]] | |||
[[Category: Gaffney K]] | |||
[[Category: Gao T]] | |||
[[Category: Han A]] | |||
[[Category: He J]] | |||
[[Category: Jayathilaka N]] | |||
[[Category: Petasis NA]] | |||
[[Category: Ye J]] | |||
Latest revision as of 12:01, 6 September 2023
Inhibiting the Binding of Class IIa Histone Deacetylases to Myocyte Enhancer Factor-2 by Small MoleculesInhibiting the Binding of Class IIa Histone Deacetylases to Myocyte Enhancer Factor-2 by Small Molecules
Structural highlights
DiseaseMEF2A_HUMAN Defects in MEF2A are a cause of coronary artery disease, autosomal dominant, type 1 (ADCAD1) [MIM:608320. A common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction. FunctionMEF2A_HUMAN Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific genes. Also involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. In cerebellar granule neurons, phosphorylated and sumoylated MEF2A represses transcription of NUR77 promoting synaptic differentiation.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedEnzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA. We used X-ray crystallography and (19)F NMR to show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development. Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.,Jayathilaka N, Han A, Gaffney KJ, Dey R, Jarusiewicz JA, Noridomi K, Philips MA, Lei X, He J, Ye J, Gao T, Petasis NA, Chen L Nucleic Acids Res. 2012 Mar 6. PMID:22396528[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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