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PDBsum entry 6f5l
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PDB id:
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Hydrolase
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Title:
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X-ray structure of human glutamate carboxypeptidase ii (gcpii) in complex with a inhibitor jhu2379
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Structure:
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Glutamate carboxypeptidase 2. Chain: a. 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,psma,pteroylpoly-gamma-glutamate carboxypeptidase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: folh1, folh, naalad1, psm, psma, gig27. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Expression_system_cell_line: schneiders s2 cells.
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Resolution:
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1.63Å
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R-factor:
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0.155
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R-free:
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0.174
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Authors:
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C.Barinka,Z.Novakova,L.Motlova
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Key ref:
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C.Barinka
et al.
(2019).
Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors.
Bioorg Med Chem,
27,
255-264.
PubMed id:
DOI:
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Date:
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01-Dec-17
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Release date:
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12-Dec-18
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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.
693 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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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
27:255-264
(2019)
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PubMed id:
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Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors.
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C.Barinka,
Z.Novakova,
N.Hin,
D.Bím,
D.V.Ferraris,
B.Duvall,
G.Kabarriti,
R.Tsukamoto,
M.Budesinsky,
L.Motlova,
C.Rojas,
B.S.Slusher,
T.A.Rokob,
L.Rulíšek,
T.Tsukamoto.
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ABSTRACT
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A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII)
were designed and synthesized using ZJ-43,
N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-l-glutamic acid, as a
molecular template in order to better understand the impact of replacing one of
the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom.
Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than
compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid)
despite GCPII's preference for peptides containing an N-terminal glutamate as
substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two
carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt
a nearly identical binding mode while (R,S)-carbamate analog 8 containing a
d-leucine forms a less extensive hydrogen bonding network. QM and QM/MM
calculations have identified no specific interactions in the GCPII active site
that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher
potency of ZJ-43 and compound 7 to the free energy changes associated with the
transfer of the ligand from bulk solvent to the protein active site as a result
of the lower ligand strain energy and solvation/desolvation energy. Our findings
underscore a broader range of factors that need to be taken into account in
predicting ligand-protein binding affinity. These insights should be of
particular importance in future efforts to design and develop GCPII inhibitors
for optimal inhibitory potency.
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