OCA at 16:02, 29 November 2023

OCA — Wed, 29 Nov 2023 16:02:48 GMT

←Older revision		Revision as of 16:02, 29 November 2023
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	==Crystal structure of PDE4D catalytic domain in complex with Apremilast==		==Crystal structure of PDE4D catalytic domain in complex with Apremilast==
-	<StructureSection load='7cbq' size='340' side='right'caption='[[7cbq]]' scene=''>	+	<StructureSection load='7cbq' size='340' side='right'caption='[[7cbq]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CBQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CBQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7cbq]] 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=7CBQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CBQ FirstGlance]. <br>
-	</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=7cbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cbq OCA], [https://pdbe.org/7cbq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cbq RCSB], [https://www.ebi.ac.uk/pdbsum/7cbq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cbq ProSAT]</span></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]] 1.59Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A9L:N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide'>A9L</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'>[https://proteopedia.org/fgij/fg.htm?mol=7cbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cbq OCA], [https://pdbe.org/7cbq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cbq RCSB], [https://www.ebi.ac.uk/pdbsum/7cbq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cbq ProSAT]</span></td></tr>
	</table>		</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 kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-alpha release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.
		+
		+	Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.,Zhang R, Li H, Zhang X, Li J, Su H, Lu Q, Dong G, Dou H, Fan C, Gu Z, Mu Q, Tang W, Xu Y, Liu H Eur J Med Chem. 2021 Feb 5;211:113004. doi: 10.1016/j.ejmech.2020.113004. Epub, 2020 Nov 7. PMID:33218684<ref>PMID:33218684</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7cbq" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphodiesterase 3D structures\|Phosphodiesterase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Xu YC]]		[[Category: Xu YC]]
	[[Category: Zhang XL]]		[[Category: Zhang XL]]

OCA at 07:57, 27 January 2021

OCA — Wed, 27 Jan 2021 07:57:07 GMT

←Older revision		Revision as of 07:57, 27 January 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 7cbq ~~is ON HOLD until Paper Publication~~	+	==Crystal structure of PDE4D catalytic domain in complex with Apremilast==
-		+	<StructureSection load='7cbq' size='340' side='right'caption='[[7cbq]]' scene=''>
-	~~Authors~~: ~~Zhang~~, X.L., Xu, Y.C.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CBQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CBQ FirstGlance]. <br>
-	~~Description: Crystal structure of PDE4D catalytic domain in complex with Apremilast~~	+	</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=7cbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cbq OCA], [https://pdbe.org/7cbq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cbq RCSB], [https://www.ebi.ac.uk/pdbsum/7cbq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cbq ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Zhang, X.L~~]]	+	__TOC__
-	[[Category: ~~Xu, Y.C~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Xu YC]]
		+	[[Category: Zhang XL]]

OCA at 05:06, 9 December 2020

OCA — Wed, 09 Dec 2020 05:06:08 GMT

←Older revision		Revision as of 05:06, 9 December 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7cbq is ON HOLD	+	The entry 7cbq is ON HOLD until Paper Publication

	Authors: Zhang, X.L., Xu, Y.C.		Authors: Zhang, X.L., Xu, Y.C.

OCA: Protected "7cbq" [edit=sysop:move=sysop]

OCA — Wed, 24 Jun 2020 18:51:37 GMT

Protected "7cbq" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:51, 24 June 2020

OCA: New page: '''Unreleased structure''' The entry 7cbq is ON HOLD Authors: Zhang, X.L., Xu, Y.C. Description: Crystal structure of PDE4D catalytic domain in complex with Apremilast [[Category: Unre...

OCA — Wed, 24 Jun 2020 18:51:36 GMT

New page: '''Unreleased structure''' The entry 7cbq is ON HOLD Authors: Zhang, X.L., Xu, Y.C. Description: Crystal structure of PDE4D catalytic domain in complex with Apremilast [[Category: Unre...

New page

'''Unreleased structure'''

The entry 7cbq is ON HOLD

Authors: Zhang, X.L., Xu, Y.C.

Description: Crystal structure of PDE4D catalytic domain in complex with Apremilast
[[Category: Unreleased Structures]]
[[Category: Zhang, X.L]]
[[Category: Xu, Y.C]]

7cbq - Revision history

OCA at 16:02, 29 November 2023

OCA at 07:57, 27 January 2021

OCA at 05:06, 9 December 2020

OCA: Protected "7cbq" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7cbq is ON HOLD Authors: Zhang, X.L., Xu, Y.C. Description: Crystal structure of PDE4D catalytic domain in complex with Apremilast [[Category: Unre...