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PDBsum entry 6gl9
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PDB id:
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Transferase
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Title:
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Crystal structure of jak3 in complex with compound 10 (fm475)
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Structure:
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Tyrosine-protein kinase jak3. Chain: a, b. Synonym: janus kinase 3,jak-3,leukocyte janus kinase,l-jak. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: jak3. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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1.70Å
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R-factor:
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0.209
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R-free:
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0.244
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Authors:
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A.Chaikuad,M.Forster,F.Von Delft,A.M.Edwards,C.H.Arrowsmith, C.Bountra,S.A.Laufer,S.Knapp,Structural Genomics Consortium (Sgc)
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Key ref:
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M.Forster
et al.
(2018).
Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold.
J Med Chem,
61,
5350-5366.
PubMed id:
DOI:
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Date:
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23-May-18
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Release date:
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27-Jun-18
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PROCHECK
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Headers
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References
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P52333
(JAK3_HUMAN) -
Tyrosine-protein kinase JAK3 from Homo sapiens
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Seq:
Struc:
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1124 a.a.
292 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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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
61:5350-5366
(2018)
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PubMed id:
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Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold.
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M.Forster,
A.Chaikuad,
T.Dimitrov,
E.Döring,
J.Holstein,
B.T.Berger,
M.Gehringer,
K.Ghoreschi,
S.Müller,
S.Knapp,
S.A.Laufer.
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ABSTRACT
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Janus kinases are major drivers of immune signaling and have been the focus of
anti-inflammatory drug discovery for more than a decade. Because of the
invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question
if selective JAK3 inhibition is sufficient to effectively block downstream
signaling has been highly controversial. Recently, we discovered the
covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome
selectivity. Crystallography revealed that this inhibitor induces an
unprecedented binding pocket by interactions of a nitrile substituent with
arginine residues in JAK3. Herein, we describe detailed structure-activity
relationships necessary for induction of the arginine pocket and the impact of
this structural change on potency, isoform selectivity, and efficacy in cellular
models. Furthermore, we evaluated the stability of this novel inhibitor class in
in vitro metabolic assays and were able to demonstrate an adequate stability of
key compound 23 for in vivo use.
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