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==A high resolution crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DCFBD, a urea-based inhibitor== | ==A high resolution crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DCFBD, a urea-based inhibitor== | ||
<StructureSection load='3d7d' size='340' side='right' caption='[[3d7d]], [[Resolution|resolution]] 1.69Å' scene=''> | <StructureSection load='3d7d' size='340' side='right'caption='[[3d7d]], [[Resolution|resolution]] 1.69Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3d7d]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3d7d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D7D 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=FBD:N-({(1R)-1-CARBOXY-2-[(4-FLUOROBENZYL)SULFANYL]ETHYL}CARBAMOYL)-L-GLUTAMIC+ACID'>FBD</scene>, <scene name='pdbligand= | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=FBD:N-({(1R)-1-CARBOXY-2-[(4-FLUOROBENZYL)SULFANYL]ETHYL}CARBAMOYL)-L-GLUTAMIC+ACID'>FBD</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">[[3d7f|3d7f]], [[3d7g|3d7g]], [[3d7h|3d7h]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3d7f|3d7f]], [[3d7g|3d7g]], [[3d7h|3d7h]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLH1, FOLH, NAALAD1, PSM, PSMA ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLH1, FOLH, NAALAD1, PSM, PSMA ([https://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'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Glutamate_carboxypeptidase_II Glutamate carboxypeptidase II], with EC number [https://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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3d7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d7d OCA], [https://pdbe.org/3d7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d7d RCSB], [https://www.ebi.ac.uk/pdbsum/3d7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d7d ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://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. | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
| Line 33: | Line 33: | ||
==See Also== | ==See Also== | ||
*[[Carboxypeptidase|Carboxypeptidase]] | *[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 40: | Line 40: | ||
[[Category: Glutamate carboxypeptidase II]] | [[Category: Glutamate carboxypeptidase II]] | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Barinka, C]] | [[Category: Barinka, C]] | ||
[[Category: Lubkowski, J]] | [[Category: Lubkowski, J]] | ||
Revision as of 10:55, 2 February 2022
A high resolution crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DCFBD, a urea-based inhibitorA high resolution crystal structure of human glutamate carboxypeptidase II (GCPII) in a complex with DCFBD, a urea-based inhibitor
Structural highlights
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 PubMedUrea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme. The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity. Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.,Barinka C, Byun Y, Dusich CL, Banerjee SR, Chen Y, Castanares M, Kozikowski AP, Mease RC, Pomper MG, Lubkowski J J Med Chem. 2008 Dec 25;51(24):7737-43. PMID:19053759[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCACategories:
- Glutamate carboxypeptidase II
- Human
- Large Structures
- Barinka, C
- Lubkowski, J
- Carboxypeptidase
- Dcfbd
- Dipeptidase
- Folate hydrolase
- Glutamate carboxypeptidase ii
- Glycoprotein
- Hydrolase
- Membrane
- Metal-binding
- Metallopeptidase
- Metalloprotease
- Multifunctional enzyme
- Naaladase
- Prostate specific membrane antigen
- Protease
- Signal-anchor
- Transmembrane
- Urea-based inhibitor