6fe5 - Revision history

OCA at 07:01, 27 March 2019

OCA — Wed, 27 Mar 2019 07:01:37 GMT

←Older revision		Revision as of 07:01, 27 March 2019
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	==X-ray structure of human glutamate carboxypeptidase II (GCPII) - the E424M inactive mutant, in complex with a inhibitor JHU 2249==		==X-ray structure of human glutamate carboxypeptidase II (GCPII) - the E424M inactive mutant, in complex with a inhibitor JHU 2249==
-	<StructureSection load='6fe5' size='340' side='right' caption='[[6fe5]], [[Resolution\|resolution]] 1.52Å' scene=''>	+	<StructureSection load='6fe5' size='340' side='right'caption='[[6fe5]], [[Resolution\|resolution]] 1.52Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6fe5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FE5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FE5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6fe5]] is a 1 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=6FE5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FE5 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=D6E:(2~{S})-2-[[(2~{S})-4-methyl-1-oxidanyl-1-oxidanylidene-pentan-2-yl]carbamoylamino]pentanedioic+acid'>D6E</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=D6E:(2~{S})-2-[[(2~{S})-4-methyl-1-oxidanyl-1-oxidanylidene-pentan-2-yl]carbamoylamino]pentanedioic+acid'>D6E</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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">FOLH1, FOLH, NAALAD1, PSM, PSMA, GIG27 ([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/Glutamate_carboxypeptidase_II Glutamate carboxypeptidase II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.21 3.4.17.21] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutamate_carboxypeptidase_II Glutamate carboxypeptidase II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.21 3.4.17.21] </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=6fe5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fe5 OCA], [http://pdbe.org/6fe5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fe5 RCSB], [http://www.ebi.ac.uk/pdbsum/6fe5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fe5 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=6fe5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fe5 OCA], [http://pdbe.org/6fe5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fe5 RCSB], [http://www.ebi.ac.uk/pdbsum/6fe5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fe5 ProSAT]</span></td></tr>
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	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/FOLH1_HUMAN FOLH1_HUMAN]] Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.		[[http://www.uniprot.org/uniprot/FOLH1_HUMAN FOLH1_HUMAN]] Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized using ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-l-glutamic acid, as a molecular template in order to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII's preference for peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt a nearly identical binding mode while (R,S)-carbamate analog 8 containing a d-leucine forms a less extensive hydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPII active site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 and compound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the protein active site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscore a broader range of factors that need to be taken into account in predicting ligand-protein binding affinity. These insights should be of particular importance in future efforts to design and develop GCPII inhibitors for optimal inhibitory potency.
		+
		+	Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors.,Barinka C, Novakova Z, Hin N, Bim D, Ferraris DV, Duvall B, Kabarriti G, Tsukamoto R, Budesinsky M, Motlova L, Rojas C, Slusher BS, Rokob TA, Rulisek L, Tsukamoto T Bioorg Med Chem. 2019 Jan 15;27(2):255-264. doi: 10.1016/j.bmc.2018.11.022. Epub , 2018 Nov 14. PMID:30552009<ref>PMID:30552009</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6fe5" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Glutamate carboxypeptidase II]]		[[Category: Glutamate carboxypeptidase II]]
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Barinka, C]]		[[Category: Barinka, C]]
	[[Category: Motlova, L]]		[[Category: Motlova, L]]

OCA at 08:20, 30 January 2019

OCA — Wed, 30 Jan 2019 08:20:34 GMT

←Older revision		Revision as of 08:20, 30 January 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 6fe5 is ON HOLD until Paper Publication~~	+	==X-ray structure of human glutamate carboxypeptidase II (GCPII) - the E424M inactive mutant, in complex with a inhibitor JHU 2249==
-		+	<StructureSection load='6fe5' size='340' side='right' caption='[[6fe5]], [[Resolution\|resolution]] 1.52Å' scene=''>
-	~~Authors: Barinka, C., Novakova, Z., Motlova, L.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6fe5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FE5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FE5 FirstGlance]. <br>
-	~~Description:~~ X-ray structure of human glutamate carboxypeptidase II (GCPII) -the E424M inactive mutant, in complex with a inhibitor JHU 2249	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=D6E:(2~{S})-2-[[(2~{S})-4-methyl-1-oxidanyl-1-oxidanylidene-pentan-2-yl]carbamoylamino]pentanedioic+acid'>D6E</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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/Glutamate_carboxypeptidase_II Glutamate carboxypeptidase II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.17.21 3.4.17.21] </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=6fe5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fe5 OCA], [http://pdbe.org/6fe5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fe5 RCSB], [http://www.ebi.ac.uk/pdbsum/6fe5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fe5 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/FOLH1_HUMAN FOLH1_HUMAN]] Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Glutamate carboxypeptidase II]]
	[[Category: Barinka, C]]		[[Category: Barinka, C]]
	[[Category: Motlova, L]]		[[Category: Motlova, L]]
	[[Category: Novakova, Z]]		[[Category: Novakova, Z]]
		+	[[Category: Hydrolase]]
		+	[[Category: Naaladase]]
		+	[[Category: Prostate-specific membrane antigen]]

OCA at 05:51, 17 January 2018

OCA — Wed, 17 Jan 2018 05:51:21 GMT

←Older revision		Revision as of 05:51, 17 January 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6fe5 is ON HOLD	+	The entry 6fe5 is ON HOLD until Paper Publication

	Authors: Barinka, C., Novakova, Z., Motlova, L.		Authors: Barinka, C., Novakova, Z., Motlova, L.
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	Description: X-ray structure of human glutamate carboxypeptidase II (GCPII) -the E424M inactive mutant, in complex with a inhibitor JHU 2249		Description: X-ray structure of human glutamate carboxypeptidase II (GCPII) -the E424M inactive mutant, in complex with a inhibitor JHU 2249
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Motlova, L]]
	[[Category: Barinka, C]]		[[Category: Barinka, C]]
		+	[[Category: Motlova, L]]
	[[Category: Novakova, Z]]		[[Category: Novakova, Z]]

OCA: Protected "6fe5" [edit=sysop:move=sysop]

OCA — Wed, 10 Jan 2018 07:17:54 GMT

Protected "6fe5" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:17, 10 January 2018

OCA: New page: '''Unreleased structure''' The entry 6fe5 is ON HOLD Authors: Barinka, C., Novakova, Z., Motlova, L. Description: X-ray structure of human glutamate carboxypeptidase II (GCPII) -the E4...

OCA — Wed, 10 Jan 2018 07:17:52 GMT

New page: '''Unreleased structure''' The entry 6fe5 is ON HOLD Authors: Barinka, C., Novakova, Z., Motlova, L. Description: X-ray structure of human glutamate carboxypeptidase II (GCPII) -the E4...

New page

'''Unreleased structure'''

The entry 6fe5 is ON HOLD

Authors: Barinka, C., Novakova, Z., Motlova, L.

Description: X-ray structure of human glutamate carboxypeptidase II (GCPII) -the E424M inactive mutant, in complex with a inhibitor JHU 2249
[[Category: Unreleased Structures]]
[[Category: Motlova, L]]
[[Category: Barinka, C]]
[[Category: Novakova, Z]]