3sjg: Difference between revisions
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==Human glutamate carboxypeptidase II (E424A inactive mutant ) in complex with N-acetyl-aspartyl-aminooctanoic acid== | ==Human glutamate carboxypeptidase II (E424A inactive mutant ) in complex with N-acetyl-aspartyl-aminooctanoic acid== | ||
<StructureSection load='3sjg' size='340' side='right' caption='[[3sjg]], [[Resolution|resolution]] 1.65Å' scene=''> | <StructureSection load='3sjg' size='340' side='right'caption='[[3sjg]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3sjg]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3sjg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SJG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SJG 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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SDR:(2S)-2-[(N-ACETYL-L-ALPHA-ASPARTYL)AMINO]NONANOIC+ACID'>SDR</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65Å</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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SDR:(2S)-2-[(N-ACETYL-L-ALPHA-ASPARTYL)AMINO]NONANOIC+ACID'>SDR</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3sjg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sjg OCA], [https://pdbe.org/3sjg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sjg RCSB], [https://www.ebi.ac.uk/pdbsum/3sjg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sjg ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3sjg" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Carboxypeptidase|Carboxypeptidase]] | *[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Alquicer | [[Category: Large Structures]] | ||
[[Category: Barinka | [[Category: Alquicer G]] | ||
[[Category: Byun | [[Category: Barinka C]] | ||
[[Category: Kim | [[Category: Byun Y]] | ||
[[Category: Konvalinka | [[Category: Kim H]] | ||
[[Category: Lubkowski | [[Category: Konvalinka J]] | ||
[[Category: Mease | [[Category: Lubkowski J]] | ||
[[Category: Mlcochova | [[Category: Mease R]] | ||
[[Category: Navratil | [[Category: Mlcochova P]] | ||
[[Category: Nemcova | [[Category: Navratil M]] | ||
[[Category: Plechanovova | [[Category: Nemcova A]] | ||
[[Category: Pomper | [[Category: Plechanovova A]] | ||
[[Category: Rulisek | [[Category: Pomper M]] | ||
[[Category: Skultetyova | [[Category: Rulisek L]] | ||
[[Category: Skultetyova L]] | |||
Latest revision as of 09:46, 27 November 2024
Human glutamate carboxypeptidase II (E424A inactive mutant ) in complex with N-acetyl-aspartyl-aminooctanoic acidHuman glutamate carboxypeptidase II (E424A inactive mutant ) in complex with N-acetyl-aspartyl-aminooctanoic acid
Structural highlights
FunctionFOLH1_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 PubMedVirtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring non-polar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of non-polar interactions governing GCPII affinity towards novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. Based on those data, we designed, synthesized and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > 0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII. Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity.,Plechanovova A, Byun Y, Alquicer G, Skultetyova L, Mlcochova P, Nemcova A, Kim HJ, Navratil M, Mease RC, Lubkowski J, Pomper MG, Konvalinka J, Rulisek L, Barinka C J Med Chem. 2011 Sep 19. PMID:21923190[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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