5wh5: Difference between revisions
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==Crystal structure of the PDE4D2 catalytic domain in complex with inhibitor (R)-Zl-n-91== | ==Crystal structure of the PDE4D2 catalytic domain in complex with inhibitor (R)-Zl-n-91== | ||
<StructureSection load='5wh5' size='340' side='right' caption='[[5wh5]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='5wh5' size='340' side='right'caption='[[5wh5]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5wh5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WH5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WH5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5wh5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WH5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WH5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=R91:1-[4-(difluoromethoxy)-3-{[(3R)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>R91</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=R91:1-[4-(difluoromethoxy)-3-{[(3R)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>R91</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE4D, DPDE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-AMP_phosphodiesterase 3',5'-cyclic-AMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.53 3.1.4.53] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-AMP_phosphodiesterase 3',5'-cyclic-AMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.53 3.1.4.53] </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=5wh5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh5 OCA], [http://pdbe.org/5wh5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wh5 RCSB], [http://www.ebi.ac.uk/pdbsum/5wh5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh5 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=5wh5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh5 OCA], [http://pdbe.org/5wh5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wh5 RCSB], [http://www.ebi.ac.uk/pdbsum/5wh5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh5 ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN]] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.<ref>PMID:15260978</ref> <ref>PMID:15576036</ref> | [[http://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN]] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.<ref>PMID:15260978</ref> <ref>PMID:15576036</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors. | |||
Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.,Feng X, Wang H, Ye M, Xu XT, Xu Y, Yang W, Zhang HT, Song G, Ke H Biochemistry. 2018 Jul 31;57(30):4518-4525. doi: 10.1021/acs.biochem.8b00336., Epub 2018 Jul 17. PMID:29975048<ref>PMID:29975048</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5wh5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Phosphodiesterase|Phosphodiesterase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: 3',5'-cyclic-AMP phosphodiesterase]] | [[Category: 3',5'-cyclic-AMP phosphodiesterase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Wang, H]] | [[Category: Wang, H]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Inhibitor]] | [[Category: Inhibitor]] | ||
[[Category: Phosphodiesterase]] | [[Category: Phosphodiesterase]] | ||
Revision as of 09:41, 31 July 2019
Crystal structure of the PDE4D2 catalytic domain in complex with inhibitor (R)-Zl-n-91Crystal structure of the PDE4D2 catalytic domain in complex with inhibitor (R)-Zl-n-91
Structural highlights
Disease[PDE4D_HUMAN] Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:614613]. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.[1] Function[PDE4D_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.[2] [3] Publication Abstract from PubMedInhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors. Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.,Feng X, Wang H, Ye M, Xu XT, Xu Y, Yang W, Zhang HT, Song G, Ke H Biochemistry. 2018 Jul 31;57(30):4518-4525. doi: 10.1021/acs.biochem.8b00336., Epub 2018 Jul 17. PMID:29975048[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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