This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

4p45

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 06:51, 15 February 2018

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a phosphoramidate inhibitor JRB-4-73

Structural highlights

4p45 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , , ,
Gene:	FOLH1, FOLH, NAALAD1, PSM, PSMA, GIG27 (HUMAN)
Activity:	Glutamate carboxypeptidase II, with EC number 3.4.17.21
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Inhibitors targeting human glutamate carboxypeptidase II (GCPII) typically consist of a P1' glutamate-derived binding module, which warrants the high affinity and specificity, linked to an effector function that is positioned within the entrance funnel of the enzyme. Here we present a comprehensive structural and computational study aimed at dissecting the importance of the effector function for GCPII binding and affinity. To this end we determined crystal structures of human GCPII in complex with a series of phosphoramidate-based inhibitors harboring effector functions of diverse physicochemical characteristics. Our data show that higher binding affinities of phosphoramidates, compared to matching phosphonates, are linked to the presence of additional hydrogen bonds between Glu424 and Gly518 of the enzyme and the amide group of the phosphoramidate. While the positioning of the P1' glutamate-derived module within the S1' pocket of GCPII is invariant, interaction interfaces between effector functions and residues lining the entrance funnel are highly varied, with the positively charged arginine patch defined by Arg463, Arg534 and Arg536 being the only 'hot-spot' common to several studied complexes. This variability stems in part from the fact that the effector/GCPII interfaces generally encompass isolated areas of nonpolar residues within the entrance funnel and resulting van der Waals contacts lack the directionality typical for hydrogen bonding interactions. The presented data unravel a complexity of binding modes of inhibitors within non-prime site(s) of GCPII and can be exploited for the design of novel GCPII-specific compounds. PDB ID CODES: Atomic coordinates of the present structures together with the experimental structure factor amplitudes were deposited at the RCSB Protein Data Bank under accession codes 4P44 (complex with JRB-4-81), 4P45 (complex with JRB-4-73), 4P4B (complex with CTT54), 4P4D (complex with MP1C), 4P4E (complex with MP1D), 4P4F (complex with NC-2-40), 4P4I (complex with T33) and 4P4J (complex with T33D).

Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities.,Novakova Z, Cerny J, Choy CJ, R Nedrow J, Choi JK, Lubkowski J, Berkman CE, Barinka C FEBS J. 2015 Oct 13. doi: 10.1111/febs.13557. PMID:26460595^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Novakova Z, Cerny J, Choy CJ, R Nedrow J, Choi JK, Lubkowski J, Berkman CE, Barinka C. Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities. FEBS J. 2015 Oct 13. doi: 10.1111/febs.13557. PMID:26460595 doi:http://dx.doi.org/10.1111/febs.13557

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4p45"

@@ Line 1: / Line 1: @@
 ==X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a phosphoramidate inhibitor JRB-4-73==
 <StructureSection load='4p45' size='340' side='right' caption='[[4p45]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4p45]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4P45 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4P45 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4p45]] 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=4P45 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4P45 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2F9:N-(4-FLUOROBENZOYL)-L-VALYL-O-[(S)-{[(1S)-1,3-DICARBOXYPROPYL]AMINO}(HYDROXY)PHOSPHORYL]-L-SERINE'>2F9</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=FUC:ALPHA-L-FUCOSE'>FUC</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></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='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=4p45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p45 OCA], [http://pdbe.org/4p45 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4p45 RCSB], [http://www.ebi.ac.uk/pdbsum/4p45 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=4p45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4p45 OCA], [http://pdbe.org/4p45 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4p45 RCSB], [http://www.ebi.ac.uk/pdbsum/4p45 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4p45 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 23: / Line 25: @@
 </StructureSection>
 [[Category: Glutamate carboxypeptidase II]]
+[[Category: Human]]
 [[Category: Barinka, C]]
 [[Category: Novakova, Z]]

4p45

From Proteopedia

Revision as of 06:51, 15 February 2018

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a phosphoramidate inhibitor JRB-4-73

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox