6zba: Difference between revisions

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==Crystal structure of PDE4D2 in complex with inhibitor LEO39652==

== Structural highlights ==

<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZBA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZBA FirstGlance]. <br>

<table><tr><td colspan='2'>[[6zba]] is a 4 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=6ZBA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZBA FirstGlance]. <br>

</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zba OCA], [http://pdbe.org/6zba PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zba RCSB], [http://www.ebi.ac.uk/pdbsum/6zba PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zba 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=QDT:2-methylpropyl+1-[8-methoxy-5-(1-oxidanylidene-3~{H}-2-benzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxylate'>QDT</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zba OCA], [http://pdbe.org/6zba PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zba RCSB], [http://www.ebi.ac.uk/pdbsum/6zba PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zba ProSAT]</span></td></tr>

</table>

== Disease ==

[[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>

== 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>

== Publication Abstract from PubMed ==

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]c yclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.,Larsen J, Lambert M, Pettersson H, Vifian T, Larsen M, Ollerstam A, Hegardt P, Eskilsson C, Laursen S, Soehoel A, Skak-Nielsen T, Hansen LM, Knudsen NO, Eirefelt S, Sorensen MD, Stilou TG, Nielsen SF J Med Chem. 2020 Oct 15. doi: 10.1021/acs.jmedchem.0c00797. PMID:33054196<ref>PMID:33054196</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

</div>

== References ==

__TOC__

</StructureSection>

[[Category: 3',5'-cyclic-AMP phosphodiesterase]]

[[Category: Human]]

[[Category: Large Structures]]

[[Category: Akutsu M]]

[[Category: Akutsu, M]]

[[Category: Hakansson M]]

[[Category: Hakansson, M]]

[[Category: Logan DT]]

[[Category: Logan, D T]]

[[Category: Sorensen MD]]

[[Category: Sorensen, M D]]

[[Category: Svensson A]]

[[Category: Svensson, A]]

[[Category: Welin M]]

[[Category: Welin, M]]

[[Category: Hydrolase]]

[[Category: Phosphodiesterase]]

[[Category: Phosphodiesterase inhibitor]]

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@@ Line 1: / Line 1: @@
 ==Crystal structure of PDE4D2 in complex with inhibitor LEO39652==
-<StructureSection load='6zba' size='340' side='right'caption='[[6zba]]' scene=''>
+<StructureSection load='6zba' size='340' side='right'caption='[[6zba]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZBA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZBA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6zba]] is a 4 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=6ZBA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZBA FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zba OCA], [http://pdbe.org/6zba PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zba RCSB], [http://www.ebi.ac.uk/pdbsum/6zba PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zba 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=QDT:2-methylpropyl+1-[8-methoxy-5-(1-oxidanylidene-3~{H}-2-benzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxylate'>QDT</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zba OCA], [http://pdbe.org/6zba PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zba RCSB], [http://www.ebi.ac.uk/pdbsum/6zba PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zba ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[[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>
+== 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.
+Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]c yclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.,Larsen J, Lambert M, Pettersson H, Vifian T, Larsen M, Ollerstam A, Hegardt P, Eskilsson C, Laursen S, Soehoel A, Skak-Nielsen T, Hansen LM, Knudsen NO, Eirefelt S, Sorensen MD, Stilou TG, Nielsen SF J Med Chem. 2020 Oct 15. doi: 10.1021/acs.jmedchem.0c00797. PMID:33054196<ref>PMID:33054196</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6zba" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: 3',5'-cyclic-AMP phosphodiesterase]]
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Akutsu M]]
+[[Category: Akutsu, M]]
-[[Category: Hakansson M]]
+[[Category: Hakansson, M]]
-[[Category: Logan DT]]
+[[Category: Logan, D T]]
-[[Category: Sorensen MD]]
+[[Category: Sorensen, M D]]
-[[Category: Svensson A]]
+[[Category: Svensson, A]]
-[[Category: Welin M]]
+[[Category: Welin, M]]
+[[Category: Hydrolase]]
+[[Category: Phosphodiesterase]]
+[[Category: Phosphodiesterase inhibitor]]