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PDBsum entry 6pl2
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PDB id:
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Transferase
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Title:
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Trk-a in complex with ligand 1a
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Structure:
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High affinity nerve growth factor receptor. Chain: a. Fragment: kinase domain. Synonym: neurotrophic tyrosine kinase receptor type 1,trk1- transforming tyrosine kinase protein,tropomyosin-related kinase a, tyrosine kinase receptor,tyrosine kinase receptor a,trk-a,gp140trk, p140-trka. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ntrk1, mtc, trk, trka. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.59Å
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R-factor:
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0.202
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R-free:
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0.274
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Authors:
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G.Subramanian
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Key ref:
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G.Subramanian
et al.
(2019).
Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).
Bioorg Med Chem Lett,
29,
126624.
PubMed id:
DOI:
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Date:
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30-Jun-19
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Release date:
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04-Sep-19
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PROCHECK
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Headers
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References
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P04629
(NTRK1_HUMAN) -
High affinity nerve growth factor receptor from Homo sapiens
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Seq:
Struc:
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796 a.a.
297 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.2.7.10.1
- receptor 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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Bioorg Med Chem Lett
29:126624
(2019)
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PubMed id:
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Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).
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G.Subramanian,
S.J.Bowen,
Y.Zhu,
N.Roush,
T.Zachary,
C.Javens,
T.Williams,
A.Janssen,
A.Gonzales.
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ABSTRACT
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In silico virtual screening using the ligand-based ROCS approach and the
commercially purchasable compound collection from the ZINC database resulted in
the identification of distinctly different and novel acetamide core frameworks
with series representatives 1a and 2a exhibiting nanomolar affinity in the
kinase domain only hTrkA HTRF biochemical assay. Additional experimental
validation using the Caliper technology with either the active or inactive
kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the
kinase inactive state. X-ray structural analysis of the kinase domain of
hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the
inactive state and to exhibit a type 2 binding mode with the DFG-out and
αC-helix out conformation. The leads also demonstrated sub-micromolar activity
in the full length hTrkA cell-based assay and selectivity against the closely
related hTrkB isoform. However, the poor microsomal stability and permeability
of the leads is suggestive of a multiparametric lead optimization effort
requirement for further progression.
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Links
