6imi - Revision history

OCA at 10:33, 27 March 2024

OCA — Wed, 27 Mar 2024 10:33:55 GMT

←Older revision		Revision as of 10:33, 27 March 2024
Line 3:		Line 3:
	<StructureSection load='6imi' size='340' side='right'caption='[[6imi]], [[Resolution\|resolution]] 1.46Å' scene=''>		<StructureSection load='6imi' size='340' side='right'caption='[[6imi]], [[Resolution\|resolution]] 1.46Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6imi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IMI OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6IMI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6imi]] 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=6IMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IMI FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AH6:6-ethoxy-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde'>AH6</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]] 1.46Å</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=AH6:6-ethoxy-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde'>AH6</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=6imi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6imi OCA], [~~http~~://pdbe.org/6imi PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6imi RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6imi PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6imi 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=6imi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6imi OCA], [https://pdbe.org/6imi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6imi RCSB], [https://www.ebi.ac.uk/pdbsum/6imi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6imi 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>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6imi" 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]]	+	[[Category: Su H]]
-	[[Category: Xu, Y]]	+	[[Category: Xu Y]]
-	[[Category: Zhang, X]]	+	[[Category: Zhang X]]
-	~~[[Category: Complex]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Pde4d~~]]	+

OCA at 06:47, 23 October 2019

OCA — Wed, 23 Oct 2019 06:47:34 GMT

←Older revision		Revision as of 06:47, 23 October 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6imi is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of PDE4D complexed with a novel inhibitor==
		+	<StructureSection load='6imi' size='340' side='right'caption='[[6imi]], [[Resolution\|resolution]] 1.46Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6imi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IMI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IMI FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AH6:6-ethoxy-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde'>AH6</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='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='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=6imi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6imi OCA], [http://pdbe.org/6imi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6imi RCSB], [http://www.ebi.ac.uk/pdbsum/6imi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6imi ProSAT]</span></td></tr>
		+	</table>
		+	== 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>
		+	== 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>
		+	<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.

-	~~Authors: Zhang~~, X., Su, H., Xu, Y.	+	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>

-	~~Description: Crystal structure of PDE4D complexed with~~ a ~~novel inhibitor~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6imi" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: 3',5'-cyclic-AMP phosphodiesterase]]
		+	[[Category: Large Structures]]
		+	[[Category: Su, H]]
	[[Category: Xu, Y]]		[[Category: Xu, Y]]
	[[Category: Zhang, X]]		[[Category: Zhang, X]]
-	[[Category: ~~Su, H~~]]	+	[[Category: Complex]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Inhibitor]]
		+	[[Category: Pde4d]]

OCA at 06:24, 19 December 2018

OCA — Wed, 19 Dec 2018 06:24:57 GMT

←Older revision		Revision as of 06:24, 19 December 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6imi is ON HOLD	+	The entry 6imi is ON HOLD until Paper Publication

	Authors: Zhang, X., Su, H., Xu, Y.		Authors: Zhang, X., Su, H., Xu, Y.

OCA at 10:43, 7 November 2018

OCA — Wed, 07 Nov 2018 10:43:01 GMT

←Older revision		Revision as of 10:43, 7 November 2018
Line 3:		Line 3:
	The entry 6imi is ON HOLD		The entry 6imi is ON HOLD

-	Authors: Zhang, X.L., Su, H.X., Xu, Y.C.	+	Authors: Zhang, X., Su, H., Xu, Y.

	Description: Crystal structure of PDE4D complexed with a novel inhibitor		Description: Crystal structure of PDE4D complexed with a novel inhibitor
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Su, ~~H.X~~]]	+	[[Category: Xu, Y]]
-	[[Category: Zhang, X.L]]	+	[[Category: Zhang, X]]
-	[[Category: Xu, ~~Y.C~~]]	+	[[Category: Su, H]]

OCA: Protected "6imi" [edit=sysop:move=sysop]

OCA — Wed, 31 Oct 2018 05:21:42 GMT

Protected "6imi" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:21, 31 October 2018

OCA: New page: '''Unreleased structure''' The entry 6imi is ON HOLD Authors: Zhang, X.L., Su, H.X., Xu, Y.C. Description: Crystal structure of PDE4D complexed with a novel inhibitor [[Category: Unrel...

OCA — Wed, 31 Oct 2018 05:21:41 GMT

New page: '''Unreleased structure''' The entry 6imi is ON HOLD Authors: Zhang, X.L., Su, H.X., Xu, Y.C. Description: Crystal structure of PDE4D complexed with a novel inhibitor [[Category: Unrel...

New page

'''Unreleased structure'''

The entry 6imi is ON HOLD

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

Description: Crystal structure of PDE4D complexed with a novel inhibitor
[[Category: Unreleased Structures]]
[[Category: Su, H.X]]
[[Category: Zhang, X.L]]
[[Category: Xu, Y.C]]