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PDBsum entry 3d7f
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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 (gcpii) in a complex with dcit, a urea-based inhibitor
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Structure:
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Glutamate carboxypeptidase 2. Chain: a. 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. Organism_taxid: 9606. Gene: folh1, folh, naalad1, psm, psma. Expressed in: drosophila melanogaster. Expression_system_cell_line: schneider's s2 cells.
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Resolution:
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1.54Å
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R-factor:
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0.177
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R-free:
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0.195
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Authors:
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J.Lubkowski,C.Barinka
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Key ref:
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C.Barinka
et al.
(2008).
Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
J Med Chem,
51,
7737-7743.
PubMed id:
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Date:
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21-May-08
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Release date:
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30-Dec-08
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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.
691 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
51:7737-7743
(2008)
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PubMed id:
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Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.
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C.Barinka,
Y.Byun,
C.L.Dusich,
S.R.Banerjee,
Y.Chen,
M.Castanares,
A.P.Kozikowski,
R.C.Mease,
M.G.Pomper,
J.Lubkowski.
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ABSTRACT
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Urea-based, low molecular weight ligands of glutamate carboxypeptidase II
(GCPII) have demonstrated efficacy in various models of neurological disorders
and can serve as imaging agents for prostate cancer. To enhance further
development of such compounds, we determined X-ray structures of four complexes
between human GCPII and urea-based inhibitors at high resolution. All ligands
demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme.
The ureido linkage between P1 and P1' inhibitor sites interacts with the
active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions
within the S1 pocket are defined primarily by a network of hydrogen bonds
between the P1 carboxylate group of the inhibitors and the side chains of
Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket
accessory to the S1 site that can be exploited for structure-based design of
novel GCPII inhibitors with increased lipophilicity.
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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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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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E.L.Luzina,
and
A.V.Popov
(2009).
Synthesis and anticancer activity of N-bis(trifluoromethyl)alkyl-N'-thiazolyl and N-bis(trifluoromethyl)alkyl-N'-benzothiazolyl ureas.
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Eur J Med Chem,
44,
4944-4953.
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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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Y.Chen,
S.Dhara,
S.R.Banerjee,
Y.Byun,
M.Pullambhatla,
R.C.Mease,
and
M.G.Pomper
(2009).
A low molecular weight PSMA-based fluorescent imaging agent for cancer.
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Biochem Biophys Res Commun,
390,
624-629.
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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
