5k32

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==PDE4D crystal structure in complex with small molecule inhibitor==
==PDE4D crystal structure in complex with small molecule inhibitor==
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<StructureSection load='5k32' size='340' side='right' caption='[[5k32]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
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<StructureSection load='5k32' size='340' side='right'caption='[[5k32]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5k32]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K32 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K32 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5k32]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K32 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K32 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Q2:4-[(3-METHOXYPHENYL)AMINO]-2-PHENYL-7,8-DIHYDRO-1,6-NAPHTHYRIDIN-5(6H)-ONE'>6Q2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Q2:4-[(3-METHOXYPHENYL)AMINO]-2-PHENYL-7,8-DIHYDRO-1,6-NAPHTHYRIDIN-5(6H)-ONE'>6Q2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<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=5k32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k32 OCA], [http://pdbe.org/5k32 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k32 RCSB], [http://www.ebi.ac.uk/pdbsum/5k32 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k32 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5k32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k32 OCA], [https://pdbe.org/5k32 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k32 RCSB], [https://www.ebi.ac.uk/pdbsum/5k32 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k32 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://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:[http://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>
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[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 ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
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4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships.,Roberts RS, Sevilla S, Ferrer M, Taltavull J, Hernandez B, Segarra V, Gracia J, Lehner MD, Gavalda A, Andres M, Cabedo J, Vilella D, Eichhorn P, Calama E, Carcasona C, Miralpeix M J Med Chem. 2018 Mar 13. doi: 10.1021/acs.jmedchem.7b01751. PMID:29502405<ref>PMID:29502405</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5k32" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 3',5'-cyclic-AMP phosphodiesterase]]
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[[Category: Homo sapiens]]
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[[Category: Aymami, J]]
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[[Category: Large Structures]]
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[[Category: Bonin, I]]
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[[Category: Aymami J]]
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[[Category: Gracia, J]]
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[[Category: Bonin I]]
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[[Category: Hernandez, B]]
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[[Category: Gracia J]]
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[[Category: Roberts, R]]
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[[Category: Hernandez B]]
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[[Category: Segarra, V]]
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[[Category: Roberts R]]
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[[Category: Soler, M]]
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[[Category: Segarra V]]
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[[Category: Hydrolase]]
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[[Category: Soler M]]
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[[Category: Inhibitor]]
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[[Category: Phosphodiesterase]]
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Current revision

PDE4D crystal structure in complex with small molecule inhibitor

PDB ID 5k32

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