OCA at 07:29, 22 November 2023

2023-11-22T07:29:33Z

←Older revision		Revision as of 07:29, 22 November 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8k4h is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of PDE4D complexed with benzbromarone==
		+	<StructureSection load='8k4h' size='340' side='right'caption='[[8k4h]], [[Resolution\|resolution]] 1.95Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8k4h]] 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=8K4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8K4H 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]] 1.95Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=R75:[3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone'>R75</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=8k4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8k4h OCA], [https://pdbe.org/8k4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8k4h RCSB], [https://www.ebi.ac.uk/pdbsum/8k4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8k4h 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 ==
		+	Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC(50) values ranging from 0.41 to 2.46 muM. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein.

-	~~Authors: Liu~~, J.Y., Li, M~~.J.~~, Xu, Y.C.	+	Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.,Liu J, Zhang X, Chen G, Shao Q, Zou Y, Li Z, Su H, Li M, Xu Y Eur J Med Chem. 2023 Dec 15;262:115893. doi: 10.1016/j.ejmech.2023.115893. Epub , 2023 Oct 23. PMID:37918035<ref>PMID:37918035</ref>

-	~~Description: Crystal structure~~ of ~~PDE4D complexed with benzbromarone~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Li~~, M.J~~]]	+	<div class="pdbe-citations 8k4h" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Xu, Y.C~~]]	+	== References ==
-	[[Category: ~~Liu, J.Y~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Li MJ]]
		+	[[Category: Liu JY]]
		+	[[Category: Xu YC]]

OCA at 04:35, 23 August 2023

2023-08-23T04:35:03Z

←Older revision		Revision as of 04:35, 23 August 2023
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8k4h is ON HOLD	+	The entry 8k4h is ON HOLD until Paper Publication

	Authors: Liu, J.Y., Li, M.J., Xu, Y.C.		Authors: Liu, J.Y., Li, M.J., Xu, Y.C.
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	Description: Crystal structure of PDE4D complexed with benzbromarone		Description: Crystal structure of PDE4D complexed with benzbromarone
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Xu, Y.C]]
	[[Category: Li, M.J]]		[[Category: Li, M.J]]
		+	[[Category: Xu, Y.C]]
	[[Category: Liu, J.Y]]		[[Category: Liu, J.Y]]

OCA: Protected "8k4h" [edit=sysop:move=sysop]

2023-07-26T10:49:46Z

Protected "8k4h" [edit=sysop:move=sysop]

←Older revision

Revision as of 10:49, 26 July 2023

OCA: New page: '''Unreleased structure''' The entry 8k4h is ON HOLD Authors: Liu, J.Y., Li, M.J., Xu, Y.C. Description: Crystal structure of PDE4D complexed with benzbromarone [[Category: Unreleased ...

2023-07-26T10:49:45Z

New page: '''Unreleased structure''' The entry 8k4h is ON HOLD Authors: Liu, J.Y., Li, M.J., Xu, Y.C. Description: Crystal structure of PDE4D complexed with benzbromarone [[Category: Unreleased ...

New page

'''Unreleased structure'''

The entry 8k4h is ON HOLD

Authors: Liu, J.Y., Li, M.J., Xu, Y.C.

Description: Crystal structure of PDE4D complexed with benzbromarone
[[Category: Unreleased Structures]]
[[Category: Xu, Y.C]]
[[Category: Li, M.J]]
[[Category: Liu, J.Y]]

8k4h - Revision history

OCA at 07:29, 22 November 2023

OCA at 04:35, 23 August 2023

OCA: Protected "8k4h" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8k4h is ON HOLD Authors: Liu, J.Y., Li, M.J., Xu, Y.C. Description: Crystal structure of PDE4D complexed with benzbromarone [[Category: Unreleased ...