|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5vi6' size='340' side='right' caption='[[5vi6]], [[Resolution|resolution]] 1.24Å' scene=''> | | <StructureSection load='5vi6' size='340' side='right' caption='[[5vi6]], [[Resolution|resolution]] 1.24Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5vi6]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VI6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VI6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5vi6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VI6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VI6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DIO:1,4-DIETHYLENE+DIOXIDE'>DIO</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=TXG:(3S,6S,9S,15aR)-6,9-dibenzyl-3-{6,6-dihydroxy-6-[(2S)-oxiran-2-yl]hexyl}octahydro-2H-pyrido[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10(3H,12H)-tetrone'>TXG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DIO:1,4-DIETHYLENE+DIOXIDE'>DIO</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| | + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=5OM:(2S)-2-AMINO-8,8-DIHYDROXY-8-[(2S)-OXIRAN-2-YL]OCTANOIC+ACID'>5OM</scene>, <scene name='pdbligand=CPI:6-CARBOXYPIPERIDINE'>CPI</scene></td></tr> |
| | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </span></td></tr> | | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </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=5vi6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vi6 OCA], [http://pdbe.org/5vi6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vi6 RCSB], [http://www.ebi.ac.uk/pdbsum/5vi6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vi6 ProSAT]</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=5vi6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vi6 OCA], [http://pdbe.org/5vi6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vi6 RCSB], [http://www.ebi.ac.uk/pdbsum/5vi6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vi6 ProSAT]</span></td></tr> |
| Line 29: |
Line 30: |
| | [[Category: Hdac]] | | [[Category: Hdac]] |
| | [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| | + | [[Category: Hydrolase-hydrolase inhibitor complex]] |
| | [[Category: Natural product inhibitor]] | | [[Category: Natural product inhibitor]] |
| Structural highlights
5vi6 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| NonStd Res: | , |
| Activity: | Histone deacetylase, with EC number 3.5.1.98 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[HDAC8_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. May play a role in smooth muscle cell contractility.[1] [2] [3] [4]
Publication Abstract from PubMed
Trapoxin A is a microbial cyclic tetrapeptide that is an essentially irreversible inhibitor of class I histone deacetylases (HDACs). The inhibitory warhead is the alpha,beta-epoxyketone side-chain of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (l-Aoe), which mimics the side-chain of the HDAC substrate acetyl-l-lysine. We now report the crystal structure of the HDAC8-trapoxin A complex at 1.24 A resolution, revealing that the ketone moiety of l-Aoe undergoes nucleophilic attack to form a zinc-bound tetrahedral gem-diolate that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Mass spectrometry, activity measurements, and isothermal titration calorimetry confirm that trapoxin A binds tightly (Kd = 3 +/- 1 nM) and does not covalently modify the enzyme, so the epoxide moiety of l-Aoe remains intact. Comparison of the HDAC8-trapoxin A complex with the HDAC6-HC toxin complex provides new insight regarding the inhibitory potency of l-Aoe-containing natural products against class I and class II HDACs.
Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8.,Porter NJ, Christianson DW ACS Chem Biol. 2017 Aug 30. doi: 10.1021/acschembio.7b00330. PMID:28846375[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hu E, Chen Z, Fredrickson T, Zhu Y, Kirkpatrick R, Zhang GF, Johanson K, Sung CM, Liu R, Winkler J. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. J Biol Chem. 2000 May 19;275(20):15254-64. PMID:10748112 doi:http://dx.doi.org/10.1074/jbc.M908988199
- ↑ Buggy JJ, Sideris ML, Mak P, Lorimer DD, McIntosh B, Clark JM. Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem J. 2000 Aug 15;350 Pt 1:199-205. PMID:10926844
- ↑ Van den Wyngaert I, de Vries W, Kremer A, Neefs J, Verhasselt P, Luyten WH, Kass SU. Cloning and characterization of human histone deacetylase 8. FEBS Lett. 2000 Jul 28;478(1-2):77-83. PMID:10922473
- ↑ Lee H, Rezai-Zadeh N, Seto E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol Cell Biol. 2004 Jan;24(2):765-73. PMID:14701748
- ↑ Porter NJ, Christianson DW. Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8. ACS Chem Biol. 2017 Aug 30. doi: 10.1021/acschembio.7b00330. PMID:28846375 doi:http://dx.doi.org/10.1021/acschembio.7b00330
|
