7b9h
From Proteopedia
(Difference between revisions)
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==Crystal structure of the PDE4D catalytic domain in complex with GEBR-42a== | ==Crystal structure of the PDE4D catalytic domain in complex with GEBR-42a== | ||
| - | <StructureSection load='7b9h' size='340' side='right'caption='[[7b9h]]' scene=''> | + | <StructureSection load='7b9h' size='340' side='right'caption='[[7b9h]], [[Resolution|resolution]] 1.50Å' 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=7B9H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B9H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7b9h]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B9H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B9H 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=7b9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b9h OCA], [https://pdbe.org/7b9h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b9h RCSB], [https://www.ebi.ac.uk/pdbsum/7b9h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b9h 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=T3K:3-[(~{E})-1-(3-cyclopentyloxy-4-methoxy-phenyl)ethylideneamino]oxy-1-morpholin-4-yl-propan-1-one'>T3K</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 ([https://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'>[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=7b9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b9h OCA], [https://pdbe.org/7b9h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b9h RCSB], [https://www.ebi.ac.uk/pdbsum/7b9h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b9h 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 == | ||
| + | Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme. | ||
| + | |||
| + | Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.,Brullo C, Rapetti F, Abbate S, Prosdocimi T, Torretta A, Semrau M, Massa M, Alfei S, Storici P, Parisini E, Bruno O Eur J Med Chem. 2021 Jun 13;223:113638. doi: 10.1016/j.ejmech.2021.113638. PMID:34171658<ref>PMID:34171658</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7b9h" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: 3',5'-cyclic-AMP phosphodiesterase]] | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Abbate S]] | + | [[Category: Abbate, S]] |
| - | [[Category: Parisini E]] | + | [[Category: Parisini, E]] |
| - | [[Category: Torretta A]] | + | [[Category: Torretta, A]] |
| + | [[Category: Complex]] | ||
| + | [[Category: Gebr]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Phosphodiesterase 4d]] | ||
Revision as of 10:11, 7 July 2021
Crystal structure of the PDE4D catalytic domain in complex with GEBR-42a
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