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3mu6

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Revision as of 16:49, 4 August 2016

Inhibiting the Binding of Class IIa Histone Deacetylases to Myocyte Enhancer Factor-2 by Small Molecules

Structural highlights

3mu6 is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	MEF2A, MEF2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[MEF2A_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.

Function

[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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

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^[8]

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

References

↑ Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J. Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol. 1999 Jan;19(1):21-30. PMID:9858528
↑ Okamoto S, Li Z, Ju C, Scholzke MN, Mathews E, Cui J, Salvesen GS, Bossy-Wetzel E, Lipton SA. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3974-9. PMID:11904443 doi:10.1073/pnas.022036399
↑ Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, Blair LA, Marshall J, Mao Z. Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron. 2003 Apr 10;38(1):33-46. PMID:12691662
↑ Zhu B, Ramachandran B, Gulick T. Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. J Biol Chem. 2005 Aug 5;280(31):28749-60. Epub 2005 Apr 15. PMID:15834131 doi:10.1074/jbc.M502491200
↑ Riquelme C, Barthel KK, Liu X. SUMO-1 modification of MEF2A regulates its transcriptional activity. J Cell Mol Med. 2006 Jan-Mar;10(1):132-44. PMID:16563226
↑ Hietakangas V, Anckar J, Blomster HA, Fujimoto M, Palvimo JJ, Nakai A, Sistonen L. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):45-50. Epub 2005 Dec 21. PMID:16371476 doi:10.1073/pnas.0503698102
↑ Shalizi A, Gaudilliere B, Yuan Z, Stegmuller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science. 2006 Feb 17;311(5763):1012-7. PMID:16484498 doi:10.1126/science.1122513
↑ 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. Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2. Nucleic Acids Res. 2012 Mar 6. PMID:22396528 doi:10.1093/nar/gks189

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3mu6"

@@ Line 1: / Line 1: @@
 ==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]] 2.43&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3mu6]] is a 8 chain structure with sequence 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=3MU6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MU6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3mu6]] is a 8 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=3MU6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MU6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BXL:(3E)-N~8~-(2-AMINOPHENYL)-N~1~-PHENYLOCT-3-ENEDIAMIDE'>BXL</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MEF2A, MEF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MEF2A, MEF2 ([http://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=3mu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mu6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mu6 RCSB], [http://www.ebi.ac.uk/pdbsum/3mu6 PDBsum]</span></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=3mu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mu6 OCA], [http://pdbe.org/3mu6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mu6 RCSB], [http://www.ebi.ac.uk/pdbsum/3mu6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mu6 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, 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: Human]]
 [[Category: Chen, L]]
 [[Category: Dey, R]]

3mu6

From Proteopedia

Revision as of 16:49, 4 August 2016

Inhibiting the Binding of Class IIa Histone Deacetylases to Myocyte Enhancer Factor-2 by Small Molecules

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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