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7w4x
From Proteopedia
(Difference between revisions)
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==Crystal structure of PDE4D catalytic domain complexed with 17== | ==Crystal structure of PDE4D catalytic domain complexed with 17== | ||
| - | <StructureSection load='7w4x' size='340' side='right'caption='[[7w4x]]' scene=''> | + | <StructureSection load='7w4x' size='340' side='right'caption='[[7w4x]], [[Resolution|resolution]] 2.20Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W4X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7w4x]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W4X FirstGlance]. <br> |
| - | </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=7w4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w4x OCA], [https://pdbe.org/7w4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w4x RCSB], [https://www.ebi.ac.uk/pdbsum/7w4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w4x ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8G7:(2R,4S)-2-(2-hydroxyethyl)-2,6-dimethyl-4-(2-methylprop-1-enyl)-3,4-dihydropyrano[3,2-c][1,8]naphthyridin-5-one'>8G7</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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'>[https://en.wikipedia.org/wiki/3',5'-cyclic-AMP_phosphodiesterase 3',5'-cyclic-AMP phosphodiesterase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7w4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w4x OCA], [https://pdbe.org/7w4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w4x RCSB], [https://www.ebi.ac.uk/pdbsum/7w4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w4x ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[https://www.uniprot.org/uniprot/PDE4D_HUMAN 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:[https://omim.org/entry/614613 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.<ref>PMID:22464250</ref> | ||
| + | == Function == | ||
| + | [[https://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 == | ||
| + | Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4, 6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one (33a) with high inhibitory potency (IC50 = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model. | ||
| + | |||
| + | Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis.,Song Z, Huang YY, Hou KQ, Liu L, Zhou F, Huang Y, Wan G, Luo HB, Xiong XF J Med Chem. 2022 Mar 10;65(5):4238-4254. doi: 10.1021/acs.jmedchem.1c02058. Epub , 2022 Feb 21. PMID:35188767<ref>PMID:35188767</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7w4x" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: 3',5'-cyclic-AMP phosphodiesterase]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Huang Y | + | [[Category: Huang, Y Y]] |
| - | [[Category: Luo H | + | [[Category: Luo, H B]] |
| + | [[Category: 5'-cyclic phosphodiesterase 4d]] | ||
| + | [[Category: Camp-specific 3ss']] | ||
| + | [[Category: Hydrolase]] | ||
Revision as of 12:03, 23 March 2022
Crystal structure of PDE4D catalytic domain complexed with 17
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