2or4
From Proteopedia
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|PDB= 2or4 |SIZE=350|CAPTION= <scene name='initialview01'>2or4</scene>, resolution 1.62Å | |PDB= 2or4 |SIZE=350|CAPTION= <scene name='initialview01'>2or4</scene>, resolution 1.62Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QUS:(S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC+ACID'>QUS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
| - | |ACTIVITY= [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] | + | |ACTIVITY= <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> |
|GENE= FOLH1, FOLH, NAALAD1, PSM, PSMA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= FOLH1, FOLH, NAALAD1, PSM, PSMA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2or4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2or4 OCA], [http://www.ebi.ac.uk/pdbsum/2or4 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2or4 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Inhibition of glutamate carboxypeptidase II (GCPII) has been shown to be neuroprotective in multiple preclinical models in which dysregulated glutamatergic transmission is implicated. Herein, we report crystal structures of the human GCPII complexed with three glutamate mimetics/derivatives, 2-(phosphonomethyl)pentanedioic acid (2-PMPA), quisqualic acid (QA), and L-serine O-sulfate (L-SOS), at 1.72, 1.62, and 2.10 A resolution, respectively. Despite the structural differences between the distal parts of the inhibitors, all three compounds share similar binding modes in the pharmacophore (i.e., S1') pocket of GCPII, where they are stabilized by a combination of polar and van der Waals interactions. The structural diversity of the distal parts of the inhibitors leads to rearrangements of the S1' site that are necessary for efficient interactions between the enzyme and an inhibitor. The set of structures presented here, in conjunction with the available biochemical data, illustrates a flexibility of the GCPII pharmacophore pocket and highlights the structural features required for potent GCPII inhibition. These findings could facilitate the rational structure-based drug design of new GCPII inhibitors in the future. | Inhibition of glutamate carboxypeptidase II (GCPII) has been shown to be neuroprotective in multiple preclinical models in which dysregulated glutamatergic transmission is implicated. Herein, we report crystal structures of the human GCPII complexed with three glutamate mimetics/derivatives, 2-(phosphonomethyl)pentanedioic acid (2-PMPA), quisqualic acid (QA), and L-serine O-sulfate (L-SOS), at 1.72, 1.62, and 2.10 A resolution, respectively. Despite the structural differences between the distal parts of the inhibitors, all three compounds share similar binding modes in the pharmacophore (i.e., S1') pocket of GCPII, where they are stabilized by a combination of polar and van der Waals interactions. The structural diversity of the distal parts of the inhibitors leads to rearrangements of the S1' site that are necessary for efficient interactions between the enzyme and an inhibitor. The set of structures presented here, in conjunction with the available biochemical data, illustrates a flexibility of the GCPII pharmacophore pocket and highlights the structural features required for potent GCPII inhibition. These findings could facilitate the rational structure-based drug design of new GCPII inhibitors in the future. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Myocardial infarcation, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602855 602855]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Barinka, C.]] | [[Category: Barinka, C.]] | ||
[[Category: Lubkowski, J.]] | [[Category: Lubkowski, J.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: CL]] | ||
| - | [[Category: NAG]] | ||
| - | [[Category: QUS]] | ||
| - | [[Category: ZN]] | ||
[[Category: folate hydrolase]] | [[Category: folate hydrolase]] | ||
[[Category: glutamate carboxypeptidase ii]] | [[Category: glutamate carboxypeptidase ii]] | ||
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[[Category: prostate specific membrane antigen]] | [[Category: prostate specific membrane antigen]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:21:56 2008'' |
Revision as of 01:21, 31 March 2008
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| , resolution 1.62Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , , , | ||||||
| Gene: | FOLH1, FOLH, NAALAD1, PSM, PSMA (Homo sapiens) | ||||||
| Activity: | Glutamate carboxypeptidase II, with EC number 3.4.17.21 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
A high resolution crystal structure of human glutamate carboxypeptidase II in complex with quisqualic acid
Overview
Inhibition of glutamate carboxypeptidase II (GCPII) has been shown to be neuroprotective in multiple preclinical models in which dysregulated glutamatergic transmission is implicated. Herein, we report crystal structures of the human GCPII complexed with three glutamate mimetics/derivatives, 2-(phosphonomethyl)pentanedioic acid (2-PMPA), quisqualic acid (QA), and L-serine O-sulfate (L-SOS), at 1.72, 1.62, and 2.10 A resolution, respectively. Despite the structural differences between the distal parts of the inhibitors, all three compounds share similar binding modes in the pharmacophore (i.e., S1') pocket of GCPII, where they are stabilized by a combination of polar and van der Waals interactions. The structural diversity of the distal parts of the inhibitors leads to rearrangements of the S1' site that are necessary for efficient interactions between the enzyme and an inhibitor. The set of structures presented here, in conjunction with the available biochemical data, illustrates a flexibility of the GCPII pharmacophore pocket and highlights the structural features required for potent GCPII inhibition. These findings could facilitate the rational structure-based drug design of new GCPII inhibitors in the future.
About this Structure
2OR4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II., Barinka C, Rovenska M, Mlcochova P, Hlouchova K, Plechanovova A, Majer P, Tsukamoto T, Slusher BS, Konvalinka J, Lubkowski J, J Med Chem. 2007 Jul 12;50(14):3267-73. Epub 2007 Jun 14. PMID:17567119
Page seeded by OCA on Mon Mar 31 04:21:56 2008
