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| | ==Crystal structure of S39D HDAC8 in complex with a largazole analogue.== | | ==Crystal structure of S39D HDAC8 in complex with a largazole analogue.== |
| - | <StructureSection load='4rn1' size='340' side='right' caption='[[4rn1]], [[Resolution|resolution]] 2.18Å' scene=''> | + | <StructureSection load='4rn1' size='340' side='right'caption='[[4rn1]], [[Resolution|resolution]] 2.18Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rn1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RN1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RN1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rn1]] 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=4RN1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RN1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=L8G:(5R,8S,11S)-5-METHYL-8-(PROPAN-2-YL)-11-[(1E)-4-SULFANYLBUT-1-EN-1-YL]-3-THIA-7,10,14,20,21-PENTAAZATRICYCLO[14.3.1.1~2,5~]HENICOSA-1(20),2(21),16,18-TETRAENE-6,9,13-TRIONE'>L8G</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]] 2.18Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rn0|4rn0]], [[4rn2|4rn2]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=L8G:(5R,8S,11S)-5-METHYL-8-(PROPAN-2-YL)-11-[(1E)-4-SULFANYLBUT-1-EN-1-YL]-3-THIA-7,10,14,20,21-PENTAAZATRICYCLO[14.3.1.1~2,5~]HENICOSA-1(20),2(21),16,18-TETRAENE-6,9,13-TRIONE'>L8G</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4rn1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rn1 OCA], [https://pdbe.org/4rn1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rn1 RCSB], [https://www.ebi.ac.uk/pdbsum/4rn1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rn1 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=4rn1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rn1 OCA], [http://pdbe.org/4rn1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rn1 RCSB], [http://www.ebi.ac.uk/pdbsum/4rn1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rn1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HDAC8_HUMAN 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.<ref>PMID:10748112</ref> <ref>PMID:10926844</ref> <ref>PMID:10922473</ref> <ref>PMID:14701748</ref> | + | [https://www.uniprot.org/uniprot/HDAC8_HUMAN 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.<ref>PMID:10748112</ref> <ref>PMID:10926844</ref> <ref>PMID:10922473</ref> <ref>PMID:14701748</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Histone deacetylase|Histone deacetylase]] | + | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] |
| | + | *[[Hypoxia-Inducible factor 1 alpha inhibitor|Hypoxia-Inducible factor 1 alpha inhibitor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone deacetylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Christianson, D W]] | + | [[Category: Large Structures]] |
| - | [[Category: Decroos, C]] | + | [[Category: Christianson DW]] |
| - | [[Category: Arginase/deacetylase fold]] | + | [[Category: Decroos C]] |
| - | [[Category: Enzyme inhibitor complex]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Largazole analogue]]
| + | |
| - | [[Category: Metalloenzyme]]
| + | |
| - | [[Category: Thiol inhibitor]]
| + | |
| Structural highlights
4rn1 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.18Å |
| Ligands: | , , , , |
| 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
The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn(2+) ion, as observed in the X-ray crystal structure of the HDAC8-Largazole complex [Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., and Christianson, D. W. (2011) J. Am. Chem. Soc. 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a six-membered pyridine ring is also substituted (with two different orientations) for the five-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn(2+) ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in loops L1 and L2 flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8.
Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8.,Decroos C, Clausen DJ, Haines BE, Wiest O, Williams RM, Christianson DW Biochemistry. 2015 Mar 31;54(12):2126-35. doi: 10.1021/acs.biochem.5b00010. Epub , 2015 Mar 20. PMID:25793284[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Decroos C, Clausen DJ, Haines BE, Wiest O, Williams RM, Christianson DW. Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8. Biochemistry. 2015 Mar 31;54(12):2126-35. doi: 10.1021/acs.biochem.5b00010. Epub , 2015 Mar 20. PMID:25793284 doi:http://dx.doi.org/10.1021/acs.biochem.5b00010
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