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3bhx

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Revision as of 08:26, 5 August 2016

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a transition state analog of Asp-Glu

Structural highlights

3bhx is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Related:	3bi0, 3bi1
Gene:	FOLH1, FOLH, NAALAD1, PSM, PSMA (HUMAN)
Activity:	Glutamate carboxypeptidase II, with EC number 3.4.17.21
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Human glutamate carboxypeptidase II (GCPII) is involved in neuronal signal transduction and intestinal folate absorption by means of the hydrolysis of its two natural substrates, N-acetyl-aspartyl-glutamate and folyl-poly-gamma-glutamates, respectively. During the past years, tremendous efforts have been made toward the structural analysis of GCPII. Crystal structures of GCPII in complex with various ligands have provided insight into the binding of these ligands, particularly to the S1' site of the enzyme. In this article, we have extended structural characterization of GCPII to its S1 site by using dipeptide-based inhibitors that interact with both S1 and S1' sites of the enzyme. To this end, we have determined crystal structures of human GCPII in complex with phosphapeptide analogs of folyl-gamma-glutamate, aspartyl-glutamate, and gamma-glutamyl-glutamate, refined at 1.50, 1.60, and 1.67 A resolution, respectively. The S1 pocket of GCPII could be accurately defined and analyzed for the first time, and the data indicate the importance of Asn519, Arg463, Arg534, and Arg536 for recognition of the penultimate (i.e., P1) substrate residues. Direct interactions between the positively charged guanidinium groups of Arg534 and Arg536 and a P1 moiety of a substrate/inhibitor provide mechanistic explanation of GCPII preference for acidic dipeptides. Additionally, observed conformational flexibility of the Arg463 and Arg536 side chains likely regulates GCPII affinity toward different inhibitors and modulates GCPII substrate specificity. The biochemical experiments assessing the hydrolysis of several GCPII substrate derivatives modified at the P1 position, also included in this report, further complement and extend conclusions derived from the structural analysis. The data described here form an a solid foundation for the structurally aided design of novel low-molecular-weight GCPII inhibitors and imaging agents.

Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs.,Barinka C, Hlouchova K, Rovenska M, Majer P, Dauter M, Hin N, Ko YS, Tsukamoto T, Slusher BS, Konvalinka J, Lubkowski J J Mol Biol. 2008 Mar 7;376(5):1438-50. Epub 2008 Jan 5. PMID:18234225^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Barinka C, Hlouchova K, Rovenska M, Majer P, Dauter M, Hin N, Ko YS, Tsukamoto T, Slusher BS, Konvalinka J, Lubkowski J. Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs. J Mol Biol. 2008 Mar 7;376(5):1438-50. Epub 2008 Jan 5. PMID:18234225 doi:10.1016/j.jmb.2007.12.066

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3bhx"

@@ Line 1: / Line 1: @@
 ==X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a transition state analog of Asp-Glu==
 <StructureSection load='3bhx' size='340' side='right' caption='[[3bhx]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3bhx]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BHX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3BHX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3bhx]] 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=3BHX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3BHX FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BHX:(2S)-2-{[(S)-(2-CARBOXYETHYL)(HYDROXY)PHOSPHORYL]METHYL}PENTANEDIOIC+ACID'>BHX</scene>, <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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3bi0|3bi0]], [[3bi1|3bi1]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLH1, FOLH, NAALAD1, PSM, PSMA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLH1, FOLH, NAALAD1, PSM, PSMA ([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='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=3bhx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bhx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3bhx RCSB], [http://www.ebi.ac.uk/pdbsum/3bhx PDBsum]</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=3bhx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bhx OCA], [http://pdbe.org/3bhx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3bhx RCSB], [http://www.ebi.ac.uk/pdbsum/3bhx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3bhx ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3bhx ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 29: / Line 30: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3bhx" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 37: / Line 39: @@
 </StructureSection>
 [[Category: Glutamate carboxypeptidase II]]
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Barinka, C]]
 [[Category: Lubkowski, J]]

3bhx

From Proteopedia

Revision as of 08:26, 5 August 2016

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a transition state analog of Asp-Glu

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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