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PDBsum entry 5ek2
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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5ek2
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PDB id:
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| Name: |
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Oxidoreductase/oxidoreductase inhibitor
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Title:
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Crystal structure of the indoleamine 2,3-dioxygenagse 1 (ido1) complexed with nlg919 analogue
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Structure:
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Indoleamine 2,3-dioxygenase 1. Chain: a, b. Synonym: ido-1,indoleamine-pyrrole 2,3-dioxygenase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ido1, ido, indo. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.68Å
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R-factor:
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0.174
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R-free:
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0.231
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Authors:
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Y.H.Peng,J.S.Wu,S.Y.Wu
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Key ref:
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Y.H.Peng
et al.
(2016).
Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1.
J Med Chem,
59,
282-293.
PubMed id:
DOI:
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Date:
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03-Nov-15
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Release date:
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23-Dec-15
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PROCHECK
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Headers
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References
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P14902
(I23O1_HUMAN) -
Indoleamine 2,3-dioxygenase 1 from Homo sapiens
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Seq:
Struc:
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403 a.a.
374 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.1.13.11.52
- indoleamine 2,3-dioxygenase.
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Reaction:
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1.
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D-tryptophan + O2 = N-formyl-D-kynurenine
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2.
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L-tryptophan + O2 = N-formyl-L-kynurenine
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D-tryptophan
Bound ligand (Het Group name = )
matches with 54.17% similarity
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+
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O2
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=
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N-formyl-D-kynurenine
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L-tryptophan
Bound ligand (Het Group name = )
matches with 54.17% similarity
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+
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O2
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=
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N-formyl-L-kynurenine
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Cofactor:
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Heme
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Heme
Bound ligand (Het Group name =
HEM)
matches with 95.45% similarity
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
59:282-293
(2016)
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PubMed id:
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Important Hydrogen Bond Networks in Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Design Revealed by Crystal Structures of Imidazoleisoindole Derivatives with IDO1.
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Y.H.Peng,
S.H.Ueng,
C.T.Tseng,
M.S.Hung,
J.S.Song,
J.S.Wu,
F.Y.Liao,
Y.S.Fan,
M.H.Wu,
W.C.Hsiao,
C.C.Hsueh,
S.Y.Lin,
C.Y.Cheng,
C.H.Tu,
L.C.Lee,
M.F.Cheng,
K.S.Shia,
C.Shih,
S.Y.Wu.
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ABSTRACT
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Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a
therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors
have been identified, but only limited structural biology studies of IDO1
inhibitors are available to provide insights on the binding mechanism of IDO1.
In this study, we present the structure of IDO1 in complex with 24, a NLG919
analogue with potent activity. The complex structure revealed the imidazole
nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole
core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket
B to interact with the surrounding residues. Most interestingly, 24 formed an
extensive hydrogen bond network with IDO1, which is a distinct feature of
IDO1/24 complex structure and is not observed in the other IDO1 complex
structures. Further structure-activity relationship, UV spectra, and structural
biology studies of several analogues of 24 demonstrated that extensive
hydrophobic interactions and the unique hydrogen bonding network contribute to
the great potency of imidazoleisoindole derivatives. These results are expected
to facilitate the structure-based drug design of new IDO inhibitors.
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