5d29: Difference between revisions
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==X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a hydroxamate inhibitor JHU241== | ==X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a hydroxamate inhibitor JHU241== | ||
<StructureSection load='5d29' size='340' side='right' caption='[[5d29]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='5d29' size='340' side='right'caption='[[5d29]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5d29]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5D29 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5D29 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5d29]] 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=5D29 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5D29 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5Q1:4-[(2~{S})-2-CARBOXY-5-(OXIDANYLAMINO)-5-OXIDANYLIDENE-PENTYL]BENZOIC+ACID'>5Q1</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5Q1:4-[(2~{S})-2-CARBOXY-5-(OXIDANYLAMINO)-5-OXIDANYLIDENE-PENTYL]BENZOIC+ACID'>5Q1</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLH1, FOLH, NAALAD1, PSM, PSMA, GIG27 ([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='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=5d29 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5d29 OCA], [http://pdbe.org/5d29 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5d29 RCSB], [http://www.ebi.ac.uk/pdbsum/5d29 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=5d29 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5d29 OCA], [http://pdbe.org/5d29 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5d29 RCSB], [http://www.ebi.ac.uk/pdbsum/5d29 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5d29 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5d29" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5d29" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Glutamate carboxypeptidase II]] | [[Category: Glutamate carboxypeptidase II]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Barinka, C]] | [[Category: Barinka, C]] | ||
[[Category: Novakova, Z]] | [[Category: Novakova, Z]] | ||
Revision as of 13:34, 1 April 2020
X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a hydroxamate inhibitor JHU241X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a hydroxamate inhibitor JHU241
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. Publication Abstract from PubMedInhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization, and biological activity of new hydroxamic acid-based inhibitors with nanomolar affinity for human GCPII. Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel rather than the conserved glutamate-binding S1' pocket. This unique binding mode provides a mechanistic explanation for the structure-activity relationship data, most notably the lack of enantiospecificity and the tolerance for bulky/hydrophobic functions as substituents of a canonical glutarate moiety. The in vivo pharmacokinetics profile of one of the inhibitors will be presented along with analgesic efficacy data from the rat chronic constrictive injury model of neuropathic pain. Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity.,Novakova Z, Wozniak K, Jancarik A, Rais R, Wu Y, Pavlicek J, Ferraris D, Havlinova B, Ptacek J, Vavra J, Hin N, Rojas C, Majer P, Slusher BS, Tsukamoto T, Barinka C J Med Chem. 2016 Apr 25. PMID:27074627[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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