6eed - Revision history

OCA at 14:41, 13 March 2024

OCA — Wed, 13 Mar 2024 14:41:00 GMT

←Older revision		Revision as of 14:41, 13 March 2024
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	<StructureSection load='6eed' size='340' side='right'caption='[[6eed]], [[Resolution\|resolution]] 1.50Å' scene=''>		<StructureSection load='6eed' size='340' side='right'caption='[[6eed]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6eed]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Plafq Plafq~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EED OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6EED FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6eed]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_FcB1/Columbia Plasmodium falciparum FcB1/Columbia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EED OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EED FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J6A:(2R)-2-[(cyclohexylacetyl)amino]-N-hydroxy-2-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)acetamide'>J6A</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.5Å</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=6eed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eed OCA], [~~http~~://pdbe.org/6eed PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6eed RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6eed PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6eed ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J6A:(2R)-2-[(cyclohexylacetyl)amino]-N-hydroxy-2-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)acetamide'>J6A</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6eed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eed OCA], [https://pdbe.org/6eed PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eed RCSB], [https://www.ebi.ac.uk/pdbsum/6eed PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eed ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/AMP1_PLAFQ AMP1_PLAFQ]] Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC.<ref>PMID:12166515</ref> <ref>PMID:19196988</ref>	+	[https://www.uniprot.org/uniprot/AMP1_PLAFQ AMP1_PLAFQ] Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC.<ref>PMID:12166515</ref> <ref>PMID:19196988</ref>
-	~~<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.	+
-		+
-	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>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6eed" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
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	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Plafq~~]]	+	[[Category: Plasmodium falciparum FcB1/Columbia]]
-	[[Category: Drinkwater, N]]	+	[[Category: Drinkwater N]]
-	[[Category: McGowan, S]]	+	[[Category: McGowan S]]
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Hydroxamic acid]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: M1 alanyl-aminopeptidase]]~~	+
-	~~[[Category: Protease~~]]	+

OCA at 07:50, 24 April 2019

OCA — Wed, 24 Apr 2019 07:50:33 GMT

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

	==X-ray crystal structure of Pf-M1 in complex with inhibitor (6p) and catalytic zinc ion==		==X-ray crystal structure of Pf-M1 in complex with inhibitor (6p) and catalytic zinc ion==
-	<StructureSection load='6eed' size='340' side='right' caption='[[6eed]], [[Resolution\|resolution]] 1.50Å' scene=''>	+	<StructureSection load='6eed' size='340' side='right'caption='[[6eed]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6eed]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EED OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EED FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6eed]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafq Plafq]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EED OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EED FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J6A:(2R)-2-[(cyclohexylacetyl)amino]-N-hydroxy-2-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)acetamide'>J6A</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J6A:(2R)-2-[(cyclohexylacetyl)amino]-N-hydroxy-2-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)acetamide'>J6A</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6eed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eed OCA], [http://pdbe.org/6eed PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eed RCSB], [http://www.ebi.ac.uk/pdbsum/6eed PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eed 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=6eed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eed OCA], [http://pdbe.org/6eed PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eed RCSB], [http://www.ebi.ac.uk/pdbsum/6eed PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eed ProSAT]</span></td></tr>
Line 18:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 6eed" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6eed" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Aminopeptidase 3D structures\|Aminopeptidase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Plafq]]
	[[Category: Drinkwater, N]]		[[Category: Drinkwater, N]]
	[[Category: McGowan, S]]		[[Category: McGowan, S]]

OCA at 08:18, 26 December 2018

OCA — Wed, 26 Dec 2018 08:18:44 GMT

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

-	~~The entry~~ 6eed is ~~ON HOLD~~ ~~until Aug 13 2020~~	+	==X-ray crystal structure of Pf-M1 in complex with inhibitor (6p) and catalytic zinc ion==
		+	<StructureSection load='6eed' size='340' side='right' caption='[[6eed]], [[Resolution\|resolution]] 1.50Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6eed]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EED OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EED FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J6A:(2R)-2-[(cyclohexylacetyl)amino]-N-hydroxy-2-(3,4,5-trifluoro[1,1-biphenyl]-4-yl)acetamide'>J6A</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6eed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eed OCA], [http://pdbe.org/6eed PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eed RCSB], [http://www.ebi.ac.uk/pdbsum/6eed PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eed ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/AMP1_PLAFQ AMP1_PLAFQ]] Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC.<ref>PMID:12166515</ref> <ref>PMID:19196988</ref>
		+	<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-M1 in complex with inhibitor (6p) and catalytic zinc ion~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
		+	<div class="pdbe-citations 6eed" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Drinkwater, N]]		[[Category: Drinkwater, N]]
-	[[Category: ~~Mcgowan~~, S]]	+	[[Category: McGowan, S]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Hydroxamic acid]]
		+	[[Category: Inhibitor]]
		+	[[Category: M1 alanyl-aminopeptidase]]
		+	[[Category: Protease]]

OCA at 08:41, 5 September 2018

OCA — Wed, 05 Sep 2018 08:41:40 GMT

←Older revision		Revision as of 08:41, 5 September 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

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

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

OCA — Wed, 22 Aug 2018 04:45:15 GMT

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

←Older revision

Revision as of 04:45, 22 August 2018

OCA: New page: '''Unreleased structure''' The entry 6eed is ON HOLD Authors: Drinkwater, N., McGowan, S. Description: X-ray crystal structure of Pf-M1 in complex with inhibitor (6p) and catalytic zin...

OCA — Wed, 22 Aug 2018 04:45:13 GMT

New page: '''Unreleased structure''' The entry 6eed is ON HOLD Authors: Drinkwater, N., McGowan, S. Description: X-ray crystal structure of Pf-M1 in complex with inhibitor (6p) and catalytic zin...

New page

'''Unreleased structure'''

The entry 6eed is ON HOLD

Authors: Drinkwater, N., McGowan, S.

Description: X-ray crystal structure of Pf-M1 in complex with inhibitor (6p) and catalytic zinc ion
[[Category: Unreleased Structures]]
[[Category: Drinkwater, N]]
[[Category: Mcgowan, S]]