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==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with AP-1-62-A== | |||
<StructureSection load='6pzu' size='340' side='right'caption='[[6pzu]], [[Resolution|resolution]] 1.74Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6pzu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PZU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PZU FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A6I:N-[(benzyloxy)carbonyl]-L-leucyl-N-{[4-(hydroxycarbamoyl)phenyl]methyl}-L-alaninamide'>A6I</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6pzu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pzu OCA], [http://pdbe.org/6pzu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pzu RCSB], [http://www.ebi.ac.uk/pdbsum/6pzu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pzu ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket. | |||
Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6.,Osko JD, Porter NJ, Narayana Reddy PA, Xiao YC, Rokka J, Jung M, Hooker JM, Salvino JM, Christianson DW J Med Chem. 2020 Jan 9;63(1):295-308. doi: 10.1021/acs.jmedchem.9b01540. Epub, 2019 Dec 19. PMID:31793776<ref>PMID:31793776</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6pzu" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Christianson, D W]] | |||
[[Category: Osko, J D]] | |||
[[Category: Histone deacetylase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Metallohydrolase]] | |||
Revision as of 11:03, 5 February 2020
Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with AP-1-62-ACrystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with AP-1-62-A
Structural highlights
Publication Abstract from PubMedInhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket. Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6.,Osko JD, Porter NJ, Narayana Reddy PA, Xiao YC, Rokka J, Jung M, Hooker JM, Salvino JM, Christianson DW J Med Chem. 2020 Jan 9;63(1):295-308. doi: 10.1021/acs.jmedchem.9b01540. Epub, 2019 Dec 19. PMID:31793776[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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