2pvw: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 4: | Line 4: | ||
|PDB= 2pvw |SIZE=350|CAPTION= <scene name='initialview01'>2pvw</scene>, resolution 1.71Å | |PDB= 2pvw |SIZE=350|CAPTION= <scene name='initialview01'>2pvw</scene>, resolution 1.71Å | ||
|SITE= <scene name='pdbsite=AC1:Nag+Binding+Site+For+Residue+A+1755'>AC1</scene>, <scene name='pdbsite=AC2:Nag+Binding+Site+For+Residue+A+1756'>AC2</scene>, <scene name='pdbsite=AC3:Nag+Binding+Site+For+Residue+A+1757'>AC3</scene>, <scene name='pdbsite=AC4:Nag+Binding+Site+For+Residue+A+1758'>AC4</scene>, <scene name='pdbsite=AC5:Nag+Binding+Site+For+Residue+A+1767'>AC5</scene>, <scene name='pdbsite=AC6:Nag+Binding+Site+For+Residue+A+1759'>AC6</scene>, <scene name='pdbsite=AC7:Nag+Binding+Site+For+Residue+A+1760'>AC7</scene>, <scene name='pdbsite=AC8:Nag+Binding+Site+For+Residue+A+1761'>AC8</scene>, <scene name='pdbsite=AC9:Nag+Binding+Site+For+Residue+A+1763'>AC9</scene>, <scene name='pdbsite=BC1:Nag+Binding+Site+For+Residue+A+1764'>BC1</scene>, <scene name='pdbsite=BC2:Bma+Binding+Site+For+Residue+A+1765'>BC2</scene>, <scene name='pdbsite=BC3:Man+Binding+Site+For+Residue+A+1766'>BC3</scene>, <scene name='pdbsite=BC4:Zn+Binding+Site+For+Residue+A+1751'>BC4</scene>, <scene name='pdbsite=BC5:Zn+Binding+Site+For+Residue+A+1752'>BC5</scene>, <scene name='pdbsite=BC6:Ca+Binding+Site+For+Residue+A+1753'>BC6</scene>, <scene name='pdbsite=BC7:Cl+Binding+Site+For+Residue+A+1754'>BC7</scene> and <scene name='pdbsite=BC8:G88+Binding+Site+For+Residue+A+1768'>BC8</scene> | |SITE= <scene name='pdbsite=AC1:Nag+Binding+Site+For+Residue+A+1755'>AC1</scene>, <scene name='pdbsite=AC2:Nag+Binding+Site+For+Residue+A+1756'>AC2</scene>, <scene name='pdbsite=AC3:Nag+Binding+Site+For+Residue+A+1757'>AC3</scene>, <scene name='pdbsite=AC4:Nag+Binding+Site+For+Residue+A+1758'>AC4</scene>, <scene name='pdbsite=AC5:Nag+Binding+Site+For+Residue+A+1767'>AC5</scene>, <scene name='pdbsite=AC6:Nag+Binding+Site+For+Residue+A+1759'>AC6</scene>, <scene name='pdbsite=AC7:Nag+Binding+Site+For+Residue+A+1760'>AC7</scene>, <scene name='pdbsite=AC8:Nag+Binding+Site+For+Residue+A+1761'>AC8</scene>, <scene name='pdbsite=AC9:Nag+Binding+Site+For+Residue+A+1763'>AC9</scene>, <scene name='pdbsite=BC1:Nag+Binding+Site+For+Residue+A+1764'>BC1</scene>, <scene name='pdbsite=BC2:Bma+Binding+Site+For+Residue+A+1765'>BC2</scene>, <scene name='pdbsite=BC3:Man+Binding+Site+For+Residue+A+1766'>BC3</scene>, <scene name='pdbsite=BC4:Zn+Binding+Site+For+Residue+A+1751'>BC4</scene>, <scene name='pdbsite=BC5:Zn+Binding+Site+For+Residue+A+1752'>BC5</scene>, <scene name='pdbsite=BC6:Ca+Binding+Site+For+Residue+A+1753'>BC6</scene>, <scene name='pdbsite=BC7:Cl+Binding+Site+For+Residue+A+1754'>BC7</scene> and <scene name='pdbsite=BC8:G88+Binding+Site+For+Residue+A+1768'>BC8</scene> | ||
|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=G88:(2S)-2-(PHOSPHONOMETHYL)PENTANEDIOIC+ACID'>G88</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> | ||
|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=2pvw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pvw OCA], [http://www.ebi.ac.uk/pdbsum/2pvw PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2pvw RCSB]</span> | |||
}} | }} | ||
| Line 14: | Line 17: | ||
==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== | ||
| Line 28: | Line 28: | ||
[[Category: Barinka, C.]] | [[Category: Barinka, C.]] | ||
[[Category: Lubkowski, J.]] | [[Category: Lubkowski, J.]] | ||
[[Category: 2-(phosphonomethyl)pentanedioic acid]] | [[Category: 2-(phosphonomethyl)pentanedioic acid]] | ||
[[Category: 2-(pmpa)]] | [[Category: 2-(pmpa)]] | ||
| Line 41: | Line 36: | ||
[[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 04:41:23 2008'' | ||
