2or4: Difference between revisions
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New page: left|200px<br /> <applet load="2or4" size="450" color="white" frame="true" align="right" spinBox="true" caption="2or4, resolution 1.62Å" /> '''A high resolution c... |
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[[Image:2or4. | [[Image:2or4.jpg|left|200px]]<br /><applet load="2or4" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2or4" size=" | |||
caption="2or4, resolution 1.62Å" /> | caption="2or4, resolution 1.62Å" /> | ||
'''A high resolution crystal structure of human glutamate carboxypeptidase II in complex with quisqualic acid'''<br /> | '''A high resolution crystal structure of human glutamate carboxypeptidase II in complex with quisqualic acid'''<br /> | ||
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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. | ||
==About this Structure== | ==About this Structure== | ||
2OR4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG, ZN, CA, CL and QUS as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | 2OR4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=QUS:'>QUS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OR4 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: prostate specific membrane antigen]] | [[Category: prostate specific membrane antigen]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:32:36 2008'' | ||
