4zun
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of acetylpolyamine amidohydrolase from Mycoplana ramosa in complex with a thiol inhibitor== | |
| + | <StructureSection load='4zun' size='340' side='right'caption='[[4zun]], [[Resolution|resolution]] 1.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4zun]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycoplana_ramosa Mycoplana ramosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZUN 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]] 1.4Å</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=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SS9:5-[(3-AMINOPROPYL)AMINO]PENTANE-1-THIOL'>SS9</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=4zun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zun OCA], [https://pdbe.org/4zun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zun RCSB], [https://www.ebi.ac.uk/pdbsum/4zun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zun ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/APAH_MYCRA APAH_MYCRA] Involved in polyamine metabolism. Catalyzes the deacetylation of various acetylated polyamines such as N-acetylputrescine, N-acetylcadaverine, N(1)-acetylspermine, N(1)-acetylspermidine and N(8)-acetylspermidine (PubMed:8824626, PubMed:3207420). In vitro, is also able to deacetylate L-Lys(epsilon-acetyl)coumarin, but has very low activity towards the larger tetrapeptide N-acetyl-L-Arg-L-His-L-Lys(epsilon-acetyl)-L-Lys(epsilon-acetyl)coumarin (PubMed:21268586).<ref>PMID:21268586</ref> <ref>PMID:3207420</ref> <ref>PMID:8824626</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Polyamines are essential aliphatic polycations that bind to nucleic acids and accordingly are involved in a variety of cellular processes. Polyamine function can be regulated by acetylation and deacetylation, just as histone function can be regulated by lysine acetylation and deacetylation. Acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa is a zinc-dependent polyamine deacetylase that shares approximately 20% amino acid sequence identity with human histone deacetylases. We now report the X-ray crystal structures of APAH-inhibitor complexes in a new and superior crystal form that diffracts to very high resolution (1.1-1.4 A). Inhibitors include previously synthesized analogues of N(8)-acetylspermidine bearing trifluoromethylketone, thiol, and hydroxamate zinc-binding groups [Decroos, C., Bowman, C. M., and Christianson, D. W. (2013) Bioorg. Med. Chem. 21, 4530], and newly synthesized hydroxamate analogues of shorter, monoacetylated diamines, the most potent of which is the hydroxamate analogue of N-acetylcadaverine (IC50 = 68 nM). The high-resolution crystal structures of APAH-inhibitor complexes provide key inferences about the inhibition and catalytic mechanism of zinc-dependent deacetylases. For example, the trifluoromethylketone analogue of N(8)-acetylspermidine binds as a tetrahedral gem-diol that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Surprisingly, this compound is also a potent inhibitor of human histone deacetylase 8 with an IC50 of 260 nM. Crystal structures of APAH-inhibitor complexes are determined at the highest resolution of any currently existing zinc deacetylase structure and thus represent the most accurate reference points for understanding structure-mechanism and structure-inhibition relationships in this critically important enzyme family. | ||
| - | + | Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase.,Decroos C, Christianson DW Biochemistry. 2015 Aug 4;54(30):4692-703. doi: 10.1021/acs.biochem.5b00536. Epub , 2015 Jul 22. PMID:26200446<ref>PMID:26200446</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 4zun" style="background-color:#fffaf0;"></div> |
| - | [[Category: Christianson | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mycoplana ramosa]] | ||
| + | [[Category: Christianson DW]] | ||
| + | [[Category: Decroos C]] | ||
Current revision
Crystal structure of acetylpolyamine amidohydrolase from Mycoplana ramosa in complex with a thiol inhibitor
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