5l8c - Revision history

OCA at 16:11, 4 October 2023

OCA — Wed, 04 Oct 2023 16:11:03 GMT

←Older revision		Revision as of 16:11, 4 October 2023
Line 1:		Line 1:

	==Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-039==		==Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-039==
-	<StructureSection load='5l8c' size='340' side='right' caption='[[5l8c]], [[Resolution\|resolution]] 2.01Å' scene=''>	+	<StructureSection load='5l8c' size='340' side='right'caption='[[5l8c]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5l8c]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Trypanosoma_(trypanozoon)_brucei~~ Trypanosoma ~~(trypanozoon)~~ brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L8C OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5L8C FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5l8c]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L8C FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=908:4-[5-[(4~{a}~{R},8~{a}~{S})-4-oxidanylidene-3-propan-2-yl-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-yl]-2-methoxy-phenyl]-~{N}-(2-azanyl-2-oxidanylidene-ethyl)benzamide'>908</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.01Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDEB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=908:4-[5-[(4~{a}~{R},8~{a}~{S})-4-oxidanylidene-3-propan-2-yl-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-yl]-2-methoxy-phenyl]-~{N}-(2-azanyl-2-oxidanylidene-ethyl)benzamide'>908</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=5l8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8c OCA], [~~http~~://pdbe.org/5l8c PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5l8c RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5l8c PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8c 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=5l8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8c OCA], [https://pdbe.org/5l8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l8c RCSB], [https://www.ebi.ac.uk/pdbsum/5l8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8c ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/Q8WQX9_9TRYP Q8WQX9_9TRYP]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 17:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5l8c" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5l8c" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphodiesterase 3D structures\|Phosphodiesterase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Anthonyrajah, E S~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Brown, D G~~]]	+	[[Category: Trypanosoma brucei]]
-	[[Category: ~~Singh, A K~~]]	+	[[Category: Anthonyrajah ES]]
-	[[Category: ~~African trypanosomiasis~~]]	+	[[Category: Brown DG]]
-	[[Category: ~~Hydrolase]]~~	+	[[Category: Singh AK]]
-	~~[[Category: Parasitic pde]]~~	+
-	~~[[Category: Sleeping sickness~~]]	+

OCA at 08:22, 2 May 2018

OCA — Wed, 02 May 2018 08:22:21 GMT

←Older revision		Revision as of 08:22, 2 May 2018
Line 3:		Line 3:
	<StructureSection load='5l8c' size='340' side='right' caption='[[5l8c]], [[Resolution\|resolution]] 2.01Å' scene=''>		<StructureSection load='5l8c' size='340' side='right' caption='[[5l8c]], [[Resolution\|resolution]] 2.01Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5l8c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L8C FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5l8c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_(trypanozoon)_brucei Trypanosoma (trypanozoon) brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L8C FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=908:4-[5-[(4~{a}~{R},8~{a}~{S})-4-oxidanylidene-3-propan-2-yl-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-yl]-2-methoxy-phenyl]-~{N}-(2-azanyl-2-oxidanylidene-ethyl)benzamide'>908</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=908:4-[5-[(4~{a}~{R},8~{a}~{S})-4-oxidanylidene-3-propan-2-yl-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-yl]-2-methoxy-phenyl]-~{N}-(2-azanyl-2-oxidanylidene-ethyl)benzamide'>908</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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">PDEB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei])</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=5l8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8c OCA], [http://pdbe.org/5l8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l8c RCSB], [http://www.ebi.ac.uk/pdbsum/5l8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8c 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=5l8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8c OCA], [http://pdbe.org/5l8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l8c RCSB], [http://www.ebi.ac.uk/pdbsum/5l8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8c ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( Ki = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC50 = 5.5 and 6.7 muM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.
		+
		+	Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.,Blaazer AR, Singh AK, de Heuvel E, Edink E, Orrling KM, Veerman JJN, van den Bergh T, Jansen C, Balasubramaniam E, Mooij WJ, Custers H, Sijm M, Tagoe DNA, Kalejaiye TD, Munday JC, Tenor H, Matheeussen A, Wijtmans M, Siderius M, de Graaf C, Maes L, de Koning HP, Bailey DS, Sterk GJ, de Esch IJP, Brown DG, Leurs R J Med Chem. 2018 May 1. doi: 10.1021/acs.jmedchem.7b01670. PMID:29672041<ref>PMID:29672041</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5l8c" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 06:16, 14 March 2018

OCA — Wed, 14 Mar 2018 06:16:56 GMT

←Older revision		Revision as of 06:16, 14 March 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 5l8c is ON HOLD until Paper Publication~~	+	==Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-039==
-		+	<StructureSection load='5l8c' size='340' side='right' caption='[[5l8c]], [[Resolution\|resolution]] 2.01Å' scene=''>
-	~~Authors: Singh, A.K., Anthonyrajah, E.S., Brown, D.G.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5l8c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L8C FirstGlance]. <br>
-	~~Description:~~ Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-039	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=908:4-[5-[(4~{a}~{R},8~{a}~{S})-4-oxidanylidene-3-propan-2-yl-4~{a},5,8,8~{a}-tetrahydrophthalazin-1-yl]-2-methoxy-phenyl]-~{N}-(2-azanyl-2-oxidanylidene-ethyl)benzamide'>908</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GAI:GUANIDINE'>GAI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	<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=5l8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8c OCA], [http://pdbe.org/5l8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l8c RCSB], [http://www.ebi.ac.uk/pdbsum/5l8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8c ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Brown~~, D.G]]	+	</table>
-	[[Category: Anthonyrajah, E.S]]	+	__TOC__
-	[[Category: Singh, A.K]]	+	</StructureSection>
		+	[[Category: Anthonyrajah, E S]]
		+	[[Category: Brown, D G]]
		+	[[Category: Singh, A K]]
		+	[[Category: African trypanosomiasis]]
		+	[[Category: Hydrolase]]
		+	[[Category: Parasitic pde]]
		+	[[Category: Sleeping sickness]]

OCA at 21:50, 23 June 2016

OCA — Thu, 23 Jun 2016 21:50:28 GMT

←Older revision		Revision as of 21:50, 23 June 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5l8c is ON HOLD	+	The entry 5l8c is ON HOLD until Paper Publication

	Authors: Singh, A.K., Anthonyrajah, E.S., Brown, D.G.		Authors: Singh, A.K., Anthonyrajah, E.S., Brown, D.G.

OCA: Protected "5l8c" [edit=sysop:move=sysop]

OCA — Mon, 20 Jun 2016 14:01:48 GMT

Protected "5l8c" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:01, 20 June 2016

OCA: New page: '''Unreleased structure''' The entry 5l8c is ON HOLD Authors: Singh, A.K., Anthonyrajah, E.S., Brown, D.G. Description: Crystal structure of T. brucei PDE-B1 catalytic domain with inhi...

OCA — Mon, 20 Jun 2016 14:01:46 GMT

New page: '''Unreleased structure''' The entry 5l8c is ON HOLD Authors: Singh, A.K., Anthonyrajah, E.S., Brown, D.G. Description: Crystal structure of T. brucei PDE-B1 catalytic domain with inhi...

New page

'''Unreleased structure'''

The entry 5l8c is ON HOLD

Authors: Singh, A.K., Anthonyrajah, E.S., Brown, D.G.

Description: Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-039
[[Category: Unreleased Structures]]
[[Category: Brown, D.G]]
[[Category: Anthonyrajah, E.S]]
[[Category: Singh, A.K]]