5wh6 - Revision history

OCA at 14:15, 13 March 2024

OCA — Wed, 13 Mar 2024 14:15:55 GMT

←Older revision		Revision as of 14:15, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='5wh6' size='340' side='right'caption='[[5wh6]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='5wh6' size='340' side='right'caption='[[5wh6]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wh6]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WH6 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5WH6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wh6]] 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=5WH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WH6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKJ:1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>AKJ</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]] 1.6Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDE4D, DPDE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKJ:1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>AKJ</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'>[https://proteopedia.org/fgij/fg.htm?mol=5wh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh6 OCA], [https://pdbe.org/5wh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wh6 RCSB], [https://www.ebi.ac.uk/pdbsum/5wh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh6 ProSAT]</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=5wh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh6 OCA], [~~http~~://pdbe.org/5wh6 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5wh6 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5wh6 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh6 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 ==~~	+
-	Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.	+
-		+
-	Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.,Feng X, Wang H, Ye M, Xu XT, Xu Y, Yang W, Zhang HT, Song G, Ke H Biochemistry. 2018 Jul 31;57(30):4518-4525. doi: 10.1021/acs.biochem.8b00336., Epub 2018 Jul 17. PMID:29975048<ref>PMID:29975048</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5wh6" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 29:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~3',5'-cyclic-AMP phosphodiesterase]]~~	+	[[Category: Homo sapiens]]
-	~~[[Category: Human~~]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ke, H]]	+	[[Category: Ke H]]
-	[[Category: Wang, H]]	+	[[Category: Wang H]]
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Inhibitor zl-n-91]]~~	+
-	~~[[Category: Pde4d-s91 complex]]~~	+
-	~~[[Category: Phosphodiesterase~~]]	+

OCA at 09:50, 1 January 2020

OCA — Wed, 01 Jan 2020 09:50:46 GMT

←Older revision		Revision as of 09:50, 1 January 2020
Line 24:		Line 24:

	==See Also==		==See Also==
-	*[[Phosphodiesterase\|Phosphodiesterase]]	+	*[[Phosphodiesterase 3D structures\|Phosphodiesterase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:41, 31 July 2019

OCA — Wed, 31 Jul 2019 06:41:22 GMT

←Older revision		Revision as of 06:41, 31 July 2019
Line 1:		Line 1:

	==Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91)==		==Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91)==
-	<StructureSection load='5wh6' size='340' side='right' caption='[[5wh6]], [[Resolution\|resolution]] 1.60Å' scene=''>	+	<StructureSection load='5wh6' size='340' side='right'caption='[[5wh6]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wh6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WH6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wh6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WH6 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKJ:1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>AKJ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKJ:1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>AKJ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDE4D, DPDE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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=5wh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh6 OCA], [http://pdbe.org/5wh6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wh6 RCSB], [http://www.ebi.ac.uk/pdbsum/5wh6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh6 ProSAT]</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=5wh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh6 OCA], [http://pdbe.org/5wh6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wh6 RCSB], [http://www.ebi.ac.uk/pdbsum/5wh6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh6 ProSAT]</span></td></tr>
Line 12:		Line 13:
	== 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>		[[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 ==
		+	Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.
		+
		+	Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors.,Feng X, Wang H, Ye M, Xu XT, Xu Y, Yang W, Zhang HT, Song G, Ke H Biochemistry. 2018 Jul 31;57(30):4518-4525. doi: 10.1021/acs.biochem.8b00336., Epub 2018 Jul 17. PMID:29975048<ref>PMID:29975048</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5wh6" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphodiesterase\|Phosphodiesterase]]
	== References ==		== References ==
	<references/>		<references/>
Line 17:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: 3',5'-cyclic-AMP phosphodiesterase]]		[[Category: 3',5'-cyclic-AMP phosphodiesterase]]
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Ke, H]]		[[Category: Ke, H]]
	[[Category: Wang, H]]		[[Category: Wang, H]]

OCA at 07:28, 18 July 2018

OCA — Wed, 18 Jul 2018 07:28:11 GMT

←Older revision		Revision as of 07:28, 18 July 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5wh6 is ~~ON HOLD until Paper Publication~~	+	==Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91)==
-		+	<StructureSection load='5wh6' size='340' side='right' caption='[[5wh6]], [[Resolution\|resolution]] 1.60Å' scene=''>
-	~~Authors~~: Ke, H., ~~Wang~~, H.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5wh6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WH6 FirstGlance]. <br>
-	~~Description~~: ~~Crystal structure of PDE4D2~~ in ~~complex~~ with ~~inhibitor~~ (~~S_Zl~~-n-~~91)~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKJ:1-[4-(difluoromethoxy)-3-{[(3S)-oxolan-3-yl]oxy}phenyl]-3-methylbutan-1-one'>AKJ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<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=5wh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wh6 OCA], [http://pdbe.org/5wh6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wh6 RCSB], [http://www.ebi.ac.uk/pdbsum/5wh6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wh6 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>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: 3',5'-cyclic-AMP phosphodiesterase]]
		+	[[Category: Ke, H]]
	[[Category: Wang, H]]		[[Category: Wang, H]]
-	[[Category: ~~Ke, H~~]]	+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Inhibitor zl-n-91]]
		+	[[Category: Pde4d-s91 complex]]
		+	[[Category: Phosphodiesterase]]

OCA: Protected "5wh6" [edit=sysop:move=sysop]

OCA — Wed, 27 Sep 2017 14:49:04 GMT

Protected "5wh6" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:49, 27 September 2017

OCA: New page: '''Unreleased structure''' The entry 5wh6 is ON HOLD until Paper Publication Authors: Ke, H., Wang, H. Description: Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91) [[...

OCA — Wed, 27 Sep 2017 14:49:03 GMT

New page: '''Unreleased structure''' The entry 5wh6 is ON HOLD until Paper Publication Authors: Ke, H., Wang, H. Description: Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91) [[...

New page

'''Unreleased structure'''

The entry 5wh6 is ON HOLD until Paper Publication

Authors: Ke, H., Wang, H.

Description: Crystal structure of PDE4D2 in complex with inhibitor (S_Zl-n-91)
[[Category: Unreleased Structures]]
[[Category: Wang, H]]
[[Category: Ke, H]]