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PDBsum entry 3zbf
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PDB id:
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Transferase
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Title:
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Structure of human ros1 kinase domain in complex with crizotinib
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Structure:
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Proto-oncogene tyrosine-protein kinase ros. Chain: a. Fragment: kinase domain, residues 1934-2232. Synonym: proto-oncogenE C-ros, proto-oncogenE C-ros-1, receptor tyrosine kinasE C-ros oncogene 1, c-ros receptor tyrosine kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.
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Resolution:
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2.20Å
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R-factor:
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0.236
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R-free:
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0.282
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Authors:
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M.Mctigue,Y.Deng,W.Liu,A.Brooun,A.Stewart
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Key ref:
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M.M.Awad
et al.
(2013).
Acquired resistance to crizotinib from a mutation in CD74-ROS1.
N Engl J Med,
368,
2395-2401.
PubMed id:
DOI:
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Date:
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08-Nov-12
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Release date:
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12-Jun-13
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PROCHECK
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Headers
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References
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P08922
(ROS1_HUMAN) -
Proto-oncogene tyrosine-protein kinase ROS from Homo sapiens
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Seq:
Struc:
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2347 a.a.
282 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.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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N Engl J Med
368:2395-2401
(2013)
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PubMed id:
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Acquired resistance to crizotinib from a mutation in CD74-ROS1.
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M.M.Awad,
R.Katayama,
M.McTigue,
W.Liu,
Y.L.Deng,
A.Brooun,
L.Friboulet,
D.Huang,
M.D.Falk,
S.Timofeevski,
K.D.Wilner,
E.L.Lockerman,
T.M.Khan,
S.Mahmood,
J.F.Gainor,
S.R.Digumarthy,
J.R.Stone,
M.Mino-Kenudson,
J.G.Christensen,
A.J.Iafrate,
J.A.Engelman,
A.T.Shaw.
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ABSTRACT
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Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently
shown efficacy in the treatment of lung cancers with ROS1 translocations.
Resistance to crizotinib developed in a patient with metastatic lung
adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a
dramatic response to treatment. We performed a biopsy of a resistant tumor and
identified an acquired mutation leading to a glycine-to-arginine substitution at
codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the
gatekeeper residue, it confers resistance to ROS1 kinase inhibition through
steric interference with drug binding. The same resistance mutation was observed
at all the metastatic sites that were examined at autopsy, suggesting that this
mutation was an early event in the clonal evolution of resistance. (Funded by
Pfizer and others; ClinicalTrials.gov number, NCT00585195 .).
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