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PDBsum entry 4ngt
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Hydrolase/hydrolase inhibitor
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PDB id
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4ngt
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of glutamate carboxypeptidase ii in a complex with urea-based inhibitor
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Structure:
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Glutamate carboxypeptidase 2. Chain: a. Fragment: extracellular domain, unp residues 44-750. Synonym: cell growth-inhibiting gene 27 protein, folate hydrolase 1, folylpoly-gamma-glutamate carboxypeptidase, fgcp, glutamate carboxypeptidase ii, gcpii, membrane glutamate carboxypeptidase, mgcp, n-acetylated-alpha-linked acidic dipeptidase i, naaladase i, prostate-specific membrane antigen, psm, psma, pteroylpoly-gamma- glutamate carboxypeptidase.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: folh, folh1, gig27, naalad1, psm, psma. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Expression_system_cell_line: schneider 2(s2) cells.
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Resolution:
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2.31Å
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R-factor:
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0.179
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R-free:
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0.223
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Authors:
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J.Tykvart,P.Pachl
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Key ref:
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J.Tykvart
et al.
(2014).
Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.
Bioorg Med Chem,
22,
4099-4108.
PubMed id:
DOI:
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Date:
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02-Nov-13
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Release date:
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18-Jun-14
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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.
692 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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DOI no:
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Bioorg Med Chem
22:4099-4108
(2014)
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PubMed id:
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Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.
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J.Tykvart,
J.Schimer,
J.Bařinková,
P.Pachl,
L.Poštová-Slavětínská,
P.Majer,
J.Konvalinka,
P.Šácha.
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ABSTRACT
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Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane
antigen (PSMA), is an established prostate cancer marker and is considered a
promising target for specific anticancer drug delivery. Low-molecular-weight
inhibitors of GCPII are advantageous specific ligands for this purpose. However,
they must be modified with a linker to enable connection of the ligand with an
imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a
structure-activity relationship (SAR) study of GCPII inhibitors with linkers
suitable for imaging and drug delivery. Structure-assisted inhibitor design and
targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki
value compared to the parent structure. X-ray structural analysis of the
inhibitor series led to the identification of several inhibitor binding modes.
We also optimized the length of the inhibitor linker for effective attachment to
a biotin-binding molecule and showed that the optimized inhibitor could be used
to target nanoparticles to cells expressing GCPII.
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Links
