6ee2 - Revision history

OCA at 14:40, 13 March 2024

2024-03-13T14:40:53Z

←Older revision		Revision as of 14:40, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6ee2' size='340' side='right'caption='[[6ee2]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='6ee2' size='340' side='right'caption='[[6ee2]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6ee2]] is a 12 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Plasmodium_falciparum_nf135~~/5.~~c10~~ Plasmodium falciparum ~~nf135~~/5.~~c10~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EE2 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6EE2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6ee2]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_NF135/5.C10 Plasmodium falciparum NF135/5.C10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EE2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EE2 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J1V:N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]cyclohexanecarboxamide'>J1V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.1Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PFNF135_05834 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1036726 Plasmodium falciparum NF135/5.C10])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J1V:N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]cyclohexanecarboxamide'>J1V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6ee2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ee2 OCA], [~~http~~://pdbe.org/6ee2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6ee2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6ee2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6ee2 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=6ee2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ee2 OCA], [https://pdbe.org/6ee2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ee2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ee2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ee2 ProSAT]</span></td></tr>
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[https://www.uniprot.org/uniprot/W4I9J7_PLAFA W4I9J7_PLAFA]
-	~~There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax~~. ~~The M1 and M17 metalloexopeptidases play key roles in Plasmodium haemoglobin digestion, and are validated drug targets~~. We used a multi-target strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterisation by co-crystallisation showed that selected compounds utilise new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.	+

-	Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases.,Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S J Med Chem. 2018 Dec 11. doi: 10.1021/acs.jmedchem.8b01310. PMID:30537832<ref>PMID:30537832</ref>	+	==See Also==
-		+	*[[Aminopeptidase 3D structures\|Aminopeptidase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6ee2" style="background-color:#fffaf0;"></div>~~	+
-	== ~~References~~ ==	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Plasmodium falciparum ~~nf135~~/5 ~~c10~~]]	+	[[Category: Plasmodium falciparum NF135/5 C10]]
-	[[Category: Drinkwater, N]]	+	[[Category: Drinkwater N]]
-	[[Category: McGowan, S]]	+	[[Category: McGowan S]]
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Hydroxamic acid]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: M17 leucyl-aminopeptidase]]~~	+
-	~~[[Category: Protease~~]]	+

OCA at 07:50, 24 April 2019

2019-04-24T07:50:17Z

←Older revision		Revision as of 07:50, 24 April 2019
Line 1:		Line 1:

	==X-ray crystal structure of Pf-M17 in complex with inhibitor 6i and regulatory zinc ion==		==X-ray crystal structure of Pf-M17 in complex with inhibitor 6i and regulatory zinc ion==
-	<StructureSection load='6ee2' size='340' side='right' caption='[[6ee2]], [[Resolution\|resolution]] 2.10Å' scene=''>	+	<StructureSection load='6ee2' size='340' side='right'caption='[[6ee2]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6ee2]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EE2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EE2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6ee2]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_nf135/5.c10 Plasmodium falciparum nf135/5.c10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EE2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EE2 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J1V:N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]cyclohexanecarboxamide'>J1V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J1V:N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]cyclohexanecarboxamide'>J1V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">PFNF135_05834 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1036726 Plasmodium falciparum NF135/5.C10])</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=6ee2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ee2 OCA], [http://pdbe.org/6ee2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ee2 RCSB], [http://www.ebi.ac.uk/pdbsum/6ee2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ee2 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=6ee2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ee2 OCA], [http://pdbe.org/6ee2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ee2 RCSB], [http://www.ebi.ac.uk/pdbsum/6ee2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ee2 ProSAT]</span></td></tr>
	</table>		</table>
Line 20:		Line 21:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Plasmodium falciparum nf135/5 c10]]
	[[Category: Drinkwater, N]]		[[Category: Drinkwater, N]]
	[[Category: McGowan, S]]		[[Category: McGowan, S]]

OCA at 08:18, 26 December 2018

2018-12-26T08:18:33Z

←Older revision		Revision as of 08:18, 26 December 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6ee2 is ~~ON HOLD until Aug 13 2020~~	+	==X-ray crystal structure of Pf-M17 in complex with inhibitor 6i and regulatory zinc ion==
		+	<StructureSection load='6ee2' size='340' side='right' caption='[[6ee2]], [[Resolution\|resolution]] 2.10Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6ee2]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EE2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EE2 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J1V:N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)ethyl]cyclohexanecarboxamide'>J1V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6ee2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ee2 OCA], [http://pdbe.org/6ee2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ee2 RCSB], [http://www.ebi.ac.uk/pdbsum/6ee2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ee2 ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium haemoglobin digestion, and are validated drug targets. We used a multi-target strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterisation by co-crystallisation showed that selected compounds utilise new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.

-	~~Authors: Drinkwater~~, N., ~~McGowan~~, S.	+	Hydroxamic acid inhibitors provide cross-species inhibition of Plasmodium M1 and M17 aminopeptidases.,Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S J Med Chem. 2018 Dec 11. doi: 10.1021/acs.jmedchem.8b01310. PMID:30537832<ref>PMID:30537832</ref>

-	~~Description: X-ray crystal structure~~ of ~~Pf-M17 in complex with inhibitor 6i and regulatory zinc ion~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
		+	<div class="pdbe-citations 6ee2" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Drinkwater, N]]		[[Category: Drinkwater, N]]
-	[[Category: ~~Mcgowan~~, S]]	+	[[Category: McGowan, S]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Hydroxamic acid]]
		+	[[Category: Inhibitor]]
		+	[[Category: M17 leucyl-aminopeptidase]]
		+	[[Category: Protease]]

OCA at 05:44, 29 August 2018

2018-08-29T05:44:38Z

←Older revision		Revision as of 05:44, 29 August 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6ee2 is ON HOLD	+	The entry 6ee2 is ON HOLD until Aug 13 2020

	Authors: Drinkwater, N., McGowan, S.		Authors: Drinkwater, N., McGowan, S.

OCA: Protected "6ee2" [edit=sysop:move=sysop]

2018-08-22T04:44:11Z

Protected "6ee2" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:44, 22 August 2018

OCA: New page: '''Unreleased structure''' The entry 6ee2 is ON HOLD Authors: Drinkwater, N., McGowan, S. Description: X-ray crystal structure of Pf-M17 in complex with inhibitor 6i and regulatory zin...

2018-08-22T04:44:10Z

New page: '''Unreleased structure''' The entry 6ee2 is ON HOLD Authors: Drinkwater, N., McGowan, S. Description: X-ray crystal structure of Pf-M17 in complex with inhibitor 6i and regulatory zin...

New page

'''Unreleased structure'''

The entry 6ee2 is ON HOLD

Authors: Drinkwater, N., McGowan, S.

Description: X-ray crystal structure of Pf-M17 in complex with inhibitor 6i and regulatory zinc ion
[[Category: Unreleased Structures]]
[[Category: Drinkwater, N]]
[[Category: Mcgowan, S]]