8d98: Difference between revisions

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OCA

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-'''Unreleased structure'''
-The entry 8d98 is ON HOLD
+==Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with fluorinated inhibitor 5==
+<StructureSection load='8d98' size='340' side='right'caption='[[8d98]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8d98]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8D98 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8D98 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]] 1.66&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=QHX:3,5-difluoro-N-hydroxybenzamide'>QHX</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=8d98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8d98 OCA], [https://pdbe.org/8d98 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8d98 RCSB], [https://www.ebi.ac.uk/pdbsum/8d98 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8d98 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/A7YT55_DANRE A7YT55_DANRE]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Bavarostat (EKZ-001) is a selective inhibitor of histone deacetylase 6 (HDAC6) that contains a meta-fluorophenylhydroxamate Zn(2+)-binding group. The recently determined crystal structure of its complex with HDAC6 from Danio rerio (zebrafish) revealed that the meta-fluoro substituent binds exclusively in an aromatic crevice defined by F583 and F643 rather than being oriented out toward solvent. To explore the binding of inhibitor C-F groups in this fluorophilic crevice, we now report a series of 10 simple fluorophenylhydroxamates bearing one or more fluorine atoms with different substitution patterns. Inhibitory potencies against human and zebrafish HDAC6 range widely from 121 to &gt;30,000 nM. The best inhibitory potency is measured for meta-difluorophenylhydroxamate (5) with IC50 = 121 nM against human HDAC6; the worst inhibitory potencies are measured for ortho-fluorophenylhydroxamate (1) as well as fluorophenylhydroxamates 4, 7, 9, and 10, although there are some variations in activity trends against human and zebrafish HDAC6. These studies show that aromatic ring fluorination at the meta position(s) does not improve inhibitory activity against human HDAC6 relative to the nonfluorinated parent compound phenylhydroxamate (IC50 = 120 nM), but meta-fluorination does not seriously compromise inhibitory activity either. Crystal structures of selected zebrafish HDAC6-fluorophenylhydroxamate complexes reveal that the fluoroaromatic ring is uniformly accommodated in the F583-F643 aromatic crevice, so ring fluorination does not perturb the inhibitor binding conformation. However, hydroxamate-Zn(2+) coordination is bidentate for some inhibitors and monodentate for others. These studies will inform design strategies underlying the design of (18)F-labeled HDAC6 inhibitors intended for positron emission tomography.
-Authors:
+Aromatic Ring Fluorination Patterns Modulate Inhibitory Potency of Fluorophenylhydroxamates Complexed with Histone Deacetylase 6.,Watson PR, Bai P, Wang C, Cragin AD, Hooker JM, Christianson DW Biochemistry. 2022 Sep 20;61(18):1945-1954. doi: 10.1021/acs.biochem.2c00332., Epub 2022 Sep 8. PMID:36073962<ref>PMID:36073962</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8d98" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Danio rerio]]
+[[Category: Large Structures]]
+[[Category: Christianson DW]]
+[[Category: Watson PR]]