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[[ | ==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=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3sjg]] is a 1 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/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>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3sje|3sje]], [[3sjf|3sjf]], [[3sjx|3sjx]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLH, FOLH1, GIG27, NAALAD1, PSM, PSMA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3sjg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sjg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sjg RCSB], [http://www.ebi.ac.uk/pdbsum/3sjg PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Virtually 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<ref>PMID:21923190</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Carboxypeptidase|Carboxypeptidase]] | *[[Carboxypeptidase|Carboxypeptidase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Glutamate carboxypeptidase II]] | [[Category: Glutamate carboxypeptidase II]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Alquicer, G | [[Category: Alquicer, G]] | ||
[[Category: Barinka, C | [[Category: Barinka, C]] | ||
[[Category: Byun, Y | [[Category: Byun, Y]] | ||
[[Category: Kim, H | [[Category: Kim, H]] | ||
[[Category: Konvalinka, J | [[Category: Konvalinka, J]] | ||
[[Category: Lubkowski, J | [[Category: Lubkowski, J]] | ||
[[Category: Mease, R | [[Category: Mease, R]] | ||
[[Category: Mlcochova, P | [[Category: Mlcochova, P]] | ||
[[Category: Navratil, M | [[Category: Navratil, M]] | ||
[[Category: Nemcova, A | [[Category: Nemcova, A]] | ||
[[Category: Plechanovova, A | [[Category: Plechanovova, A]] | ||
[[Category: Pomper, M | [[Category: Pomper, M]] | ||
[[Category: Rulisek, L | [[Category: Rulisek, L]] | ||
[[Category: Skultetyova, L | [[Category: Skultetyova, L]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Metallopeptidase]] | [[Category: Metallopeptidase]] | ||
Revision as of 14:34, 9 December 2014
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
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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