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PDBsum entry 6pl1
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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 1b
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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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2.03Å
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R-factor:
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0.220
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R-free:
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0.260
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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).
Lead identification and characterization of hTrkA type 2 inhibitors.
Bioorg Med Chem Lett,
29,
126680.
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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09-Oct-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.
290 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
29:126680
(2019)
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PubMed id:
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Lead identification and characterization of hTrkA type 2 inhibitors.
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G.Subramanian,
Y.Zhu,
S.J.Bowen,
N.Roush,
J.A.White,
D.Huczek,
T.Zachary,
C.Javens,
T.Williams,
A.Janssen,
A.Gonzales.
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ABSTRACT
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Virtual in silico structure-guided modeling, followed by in vitro biochemical
screening of a subset of commercially purchasable compound collection resulted
in the identification of several human tropomyosin receptor kinase A (hTrkA)
inhibitors that bind the orthosteric ATP site and exhibit binding preference for
the inactive kinase conformation. The type 2 binding mode with the DFG-out and
αC-helix out hTrkA kinase domain conformation was confirmed from X-ray
crystallographic solution of a representative inhibitor analog, 1b. Additional
hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth
inhibition using rat PC12 cells, early ADME profiling, and preliminary
pharmacokinetic evaluation in rodents guided the lead inhibitor progression in
the discovery screening funnel.
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