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| | <StructureSection load='6imt' size='340' side='right'caption='[[6imt]], [[Resolution|resolution]] 1.48Å' scene=''> | | <StructureSection load='6imt' size='340' side='right'caption='[[6imt]], [[Resolution|resolution]] 1.48Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6imt]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IMT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IMT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6imt]] 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=6IMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IMT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AK0:(1S)-1-[2-(6-fluoro-1H-indol-3-yl)ethyl]-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde'>AK0</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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.483Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AK0:(1S)-1-[2-(6-fluoro-1H-indol-3-yl)ethyl]-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde'>AK0</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> |
| - | <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=6imt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6imt OCA], [http://pdbe.org/6imt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6imt RCSB], [http://www.ebi.ac.uk/pdbsum/6imt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6imt ProSAT]</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=6imt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6imt OCA], [https://pdbe.org/6imt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6imt RCSB], [https://www.ebi.ac.uk/pdbsum/6imt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6imt ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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> | + | [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 == |
| - | [[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> | + | [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, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.
| + | |
| | | | |
| - | Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.,Zhang X, Dong G, Li H, Chen W, Li J, Feng C, Gu Z, Zhu F, Zhang R, Li M, Tang W, Liu H, Xu Y J Med Chem. 2019 Jun 13;62(11):5579-5593. doi: 10.1021/acs.jmedchem.9b00518. Epub, 2019 May 31. PMID:31099559<ref>PMID:31099559</ref>
| + | ==See Also== |
| - | | + | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | *[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6imt" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 3',5'-cyclic-AMP phosphodiesterase]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Su, H X]] | + | [[Category: Su HX]] |
| - | [[Category: Xu, Y C]] | + | [[Category: Xu YC]] |
| - | [[Category: Zhang, X L]] | + | [[Category: Zhang XL]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Pde4d]]
| + | |
| 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]
See Also
References
- ↑ Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot AM, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova JL, Le Merrer M, Munnich A, Cormier-Daire V. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet. 2012 Apr 6;90(4):740-5. doi: 10.1016/j.ajhg.2012.03.003. Epub, 2012 Mar 29. PMID:22464250 doi:10.1016/j.ajhg.2012.03.003
- ↑ Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, Neiman J, West BL, Zhang C, Milburn MV, Kim SH, Schlessinger J, Bollag G. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell. 2004 Jul 23;15(2):279-86. PMID:15260978 doi:http://dx.doi.org/10.1016/j.molcel.2004.07.005
- ↑ Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure. 2004 Dec;12(12):2233-47. PMID:15576036 doi:http://dx.doi.org/10.1016/j.str.2004.10.004
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