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PDBsum entry 6pmc
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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. 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: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.19Å
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R-factor:
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0.250
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R-free:
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0.298
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Authors:
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G.Subramanian,D.G.Brown
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Key ref:
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G.Subramanian
et al.
(2020).
Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA).
RSC Med Chem,
11,
370-377.
PubMed id:
DOI:
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Date:
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01-Jul-19
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Release date:
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26-Feb-20
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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.
289 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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RSC Med Chem
11:370-377
(2020)
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PubMed id:
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Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA).
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G.Subramanian,
R.Vairagoundar,
S.J.Bowen,
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 followed by in vitro biochemical,
biophysical, and cellular screening resulted in the identification of distinctly
different hTrkA kinase domain inhibitor scaffolds. X-ray structural
analysis of representative inhibitors bound to hTrkA kinase domain
defined the binding mode and rationalized the mechanism of action. Preliminary
assessment of the sub-type selectivity against the closest hTrkB isoform,
and early ADME guided the progression of select inhibitor leads in the screening
cascade. The possibility of the actives sustaining to known hTrkA
resistance mutations assessed in silico offers initial guidance into the
required multiparametric lead optimization to arrive at a clinical candidate.
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Links
