3g4l: Difference between revisions
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==Crystal structure of human phosphodiesterase 4d with roflumilast== | ==Crystal structure of human phosphodiesterase 4d with roflumilast== | ||
<StructureSection load='3g4l' size='340' side='right' caption='[[3g4l]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='3g4l' size='340' side='right' caption='[[3g4l]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3g4l]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3g4l]] 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=3G4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3G4L FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ROF:3-(CYCLOPROPYLMETHOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-(DIFLUOROMETHOXY)BENZAMIDE'>ROF</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ROF:3-(CYCLOPROPYLMETHOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-(DIFLUOROMETHOXY)BENZAMIDE'>ROF</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g45|3g45]], [[3g4g|3g4g]], [[3g4i|3g4i]], [[3g4k|3g4k]], [[3g58|3g58]], [[3gpz|3gpz]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g45|3g45]], [[3g4g|3g4g]], [[3g4i|3g4i]], [[3g4k|3g4k]], [[3g58|3g58]], [[3gpz|3gpz]]</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 | <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-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </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-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </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=3g4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g4l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3g4l RCSB], [http://www.ebi.ac.uk/pdbsum/3g4l PDBsum]</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=3g4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g4l OCA], [http://pdbe.org/3g4l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3g4l RCSB], [http://www.ebi.ac.uk/pdbsum/3g4l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3g4l ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3g4l ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3g4l" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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</StructureSection> | </StructureSection> | ||
[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | ||
[[Category: | [[Category: Human]] | ||
[[Category: Staker, B L]] | [[Category: Staker, B L]] | ||
[[Category: Camp]] | [[Category: Camp]] | ||
Revision as of 01:32, 6 August 2016
Crystal structure of human phosphodiesterase 4d with roflumilastCrystal structure of human phosphodiesterase 4d with roflumilast
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] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPhosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.,Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME Nat Biotechnol. 2010 Jan;28(1):63-70. Epub 2009 Dec 27. PMID:20037581[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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