7w4x

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of PDE4D catalytic domain complexed with 17

Structural highlights

7w4x is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2000732Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4, 6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one (33a) with high inhibitory potency (IC50 = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.

Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis.,Song Z, Huang YY, Hou KQ, Liu L, Zhou F, Huang Y, Wan G, Luo HB, Xiong XF J Med Chem. 2022 Mar 10;65(5):4238-4254. doi: 10.1021/acs.jmedchem.1c02058. Epub , 2022 Feb 21. PMID:35188767^[4]

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

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
↑ Song Z, Huang YY, Hou KQ, Liu L, Zhou F, Huang Y, Wan G, Luo HB, Xiong XF. Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis. J Med Chem. 2022 Mar 10;65(5):4238-4254. doi: 10.1021/acs.jmedchem.1c02058. Epub , 2022 Feb 21. PMID:35188767 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c02058

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7w4x"

Categories: Homo sapiens | Large Structures | Huang Y-Y | Luo H-B

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7w4x is ON HOLD
+==Crystal structure of PDE4D catalytic domain complexed with 17==
+<StructureSection load='7w4x' size='340' side='right'caption='[[7w4x]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7w4x]] 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=7W4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W4X FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2000732&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8G7:(2R,4S)-2-(2-hydroxyethyl)-2,6-dimethyl-4-(2-methylprop-1-enyl)-3,4-dihydropyrano[3,2-c][1,8]naphthyridin-5-one'>8G7</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'>[https://proteopedia.org/fgij/fg.htm?mol=7w4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w4x OCA], [https://pdbe.org/7w4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w4x RCSB], [https://www.ebi.ac.uk/pdbsum/7w4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w4x ProSAT]</span></td></tr>
+</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 ==
+Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4, 6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one (33a) with high inhibitory potency (IC50 = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.
-Authors: Huang, Y.-Y., Luo, H.-B.
+Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis.,Song Z, Huang YY, Hou KQ, Liu L, Zhou F, Huang Y, Wan G, Luo HB, Xiong XF J Med Chem. 2022 Mar 10;65(5):4238-4254. doi: 10.1021/acs.jmedchem.1c02058. Epub , 2022 Feb 21. PMID:35188767<ref>PMID:35188767</ref>
-Description: Crystal structure of PDE4D catalytic domain complexed with 17
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Luo, H.-B]]
+<div class="pdbe-citations 7w4x" style="background-color:#fffaf0;"></div>
-[[Category: Huang, Y.-Y]]
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Huang Y-Y]]
+[[Category: Luo H-B]]

7w4x

From Proteopedia

Current revision

Crystal structure of PDE4D catalytic domain complexed with 17

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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