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PDBsum entry 5a9u
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PDB id:
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Transferase
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Title:
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Structure of c1156y mutant human anaplastic lymphoma kinase in complex with pf-06463922 ((10r)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo- 10,15,16,17-tetrahydro-2h-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).
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Structure:
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Alk tyrosine kinase receptor. Chain: a. Fragment: tyrosine kinase domain, residues 1093-1411. Synonym: anaplastic lymphoma kinase. Engineered: yes. Mutation: yes. Other_details: nonphosphorylated
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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: sf9.
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Resolution:
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1.60Å
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R-factor:
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0.216
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R-free:
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0.258
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Authors:
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M.Mctigue,Y.-L.Deng,W.Liu,A.Brooun,A.Stewart
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Key ref:
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A.T.Shaw
et al.
(2016).
Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
N Engl J Med,
374,
54-61.
PubMed id:
DOI:
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Date:
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22-Jul-15
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Release date:
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08-Jun-16
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PROCHECK
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Headers
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References
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Q9UM73
(ALK_HUMAN) -
ALK tyrosine kinase receptor from Homo sapiens
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Seq:
Struc:
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1620 a.a.
293 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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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
374:54-61
(2016)
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PubMed id:
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Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
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A.T.Shaw,
L.Friboulet,
I.Leshchiner,
J.F.Gainor,
S.Bergqvist,
A.Brooun,
B.J.Burke,
Y.L.Deng,
W.Liu,
L.Dardaei,
R.L.Frias,
K.R.Schultz,
J.Logan,
L.P.James,
T.Smeal,
S.Timofeevski,
R.Katayama,
A.J.Iafrate,
L.Le,
M.McTigue,
G.Getz,
T.W.Johnson,
J.A.Engelman.
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ABSTRACT
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In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung
cancer, resistance to crizotinib developed because of a mutation in the ALK
kinase domain. This mutation is predicted to result in a substitution of
cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not
respond to a second-generation ALK inhibitor, but it did respond to lorlatinib
(PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing
of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y
mutation. The L1198F substitution confers resistance to lorlatinib through
steric interference with drug binding. However, L1198F paradoxically enhances
binding to crizotinib, negating the effect of C1156Y and resensitizing resistant
cancers to crizotinib. The patient received crizotinib again, and her
cancer-related symptoms and liver failure resolved. (Funded by Pfizer and
others; ClinicalTrials.gov number, NCT01970865.).
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Links
