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PDBsum entry 2or4
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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A high resolution crystal structure of human glutamate carboxypeptidase ii in complex with quisqualic acid
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Structure:
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Glutamate carboxypeptidase 2. Chain: a. Fragment: recombinant human gcpii, extracellular part. Synonym: glutamate carboxypeptidase ii, membrane glutamate carboxypeptidase, mgcp, n- acetylated-alpha-linked acidic dipeptidase i, naaladase i, pteroylpoly-gamma-glutamate carboxypeptidase, folylpoly-gamma- glutamate carboxypeptidase, fgcp, folate hydrolase 1, prostate- specific membrane antigen, psma, psm. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: folh1, folh, naalad1, psm, psma. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227.
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Resolution:
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1.62Å
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R-factor:
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0.186
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R-free:
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0.219
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Authors:
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C.Barinka,J.Lubkowski
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Key ref:
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C.Barinka
et al.
(2007).
Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II.
J Med Chem,
50,
3267-3273.
PubMed id:
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Date:
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01-Feb-07
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Release date:
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12-Jun-07
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PROCHECK
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Headers
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References
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Q04609
(FOLH1_HUMAN) -
Glutamate carboxypeptidase 2 from Homo sapiens
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Seq:
Struc:
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750 a.a.
689 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.17.21
- glutamate carboxypeptidase Ii.
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Reaction:
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Release of an unsubstituted, C-terminal glutamyl residue, typically from Ac-Asp-Glu or folylpoly-gamma-glutamates.
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Cofactor:
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Zn(2+)
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J Med Chem
50:3267-3273
(2007)
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PubMed id:
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Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II.
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C.Barinka,
M.Rovenská,
P.Mlcochová,
K.Hlouchová,
A.Plechanovová,
P.Majer,
T.Tsukamoto,
B.S.Slusher,
J.Konvalinka,
J.Lubkowski.
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ABSTRACT
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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.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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B.R.Blank,
P.Alayoglu,
W.Engen,
J.K.Choi,
C.E.Berkman,
and
M.O.Anderson
(2011).
N-Substituted Glutamyl Sulfonamides as Inhibitors of Glutamate Carboxypeptidase II (GCP2).
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Chem Biol Drug Des,
77,
241-247.
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R.E.Hubbard
(2011).
Structure-based drug discovery and protein targets in the CNS.
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Neuropharmacology,
60,
7.
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C.H.Küchenthal,
and
W.Maison
(2010).
Antibody recruiting small molecules: a new option for prostate tumor therapy by PSMA targeting.
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Chembiochem,
11,
1052-1054.
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H.Wang,
Y.Byun,
C.Barinka,
M.Pullambhatla,
H.E.Bhang,
J.J.Fox,
J.Lubkowski,
R.C.Mease,
and
M.G.Pomper
(2010).
Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies.
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Bioorg Med Chem Lett,
20,
392-397.
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PDB code:
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K.Hlouchova,
C.Barinka,
J.Konvalinka,
and
J.Lubkowski
(2009).
Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III.
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FEBS J,
276,
4448-4462.
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PDB codes:
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R.P.Murelli,
A.X.Zhang,
J.Michel,
W.L.Jorgensen,
and
D.A.Spiegel
(2009).
Chemical control over immune recognition: a class of antibody-recruiting small molecules that target prostate cancer.
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J Am Chem Soc,
131,
17090-17092.
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C.Barinka,
K.Hlouchova,
M.Rovenska,
P.Majer,
M.Dauter,
N.Hin,
Y.S.Ko,
T.Tsukamoto,
B.S.Slusher,
J.Konvalinka,
and
J.Lubkowski
(2008).
Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs.
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J Mol Biol,
376,
1438-1450.
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PDB codes:
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M.Rovenská,
K.Hlouchová,
P.Sácha,
P.Mlcochová,
V.Horák,
J.Zámecník,
C.Barinka,
and
J.Konvalinka
(2008).
Tissue expression and enzymologic characterization of human prostate specific membrane antigen and its rat and pig orthologs.
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Prostate,
68,
171-182.
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P.Mlcochová,
A.Plechanovová,
C.Barinka,
D.Mahadevan,
J.W.Saldanha,
L.Rulísek,
and
J.Konvalinka
(2007).
Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesis.
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FEBS J,
274,
4731-4741.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
