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Yorodumi- PDB-5aa9: Structure of L1198F Mutant Human Anaplastic Lymphoma Kinase in Co... -
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-Basic information
Entry | Database: PDB / ID: 5aa9 | ||||||
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Title | Structure of L1198F 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). | ||||||
Components | ALK TYROSINE KINASE RECEPTOR | ||||||
Keywords | TRANSFERASE / RECEPTOR TYROSINE KINASE / INHIBITOR / MUTANT | ||||||
Function / homology | Function and homology information response to environmental enrichment / ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway ...response to environmental enrichment / ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / Signaling by ALK / Signaling by ALK fusions and activated point mutants / neuron development / Nuclear events stimulated by ALK signaling in cancer / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / heparin binding / positive regulation of NF-kappaB transcription factor activity / regulation of cell population proliferation / protein tyrosine kinase activity / regulation of apoptotic process / protein autophosphorylation / receptor complex / phosphorylation / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane Similarity search - Function | ||||||
Biological species | HOMO SAPIENS (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å | ||||||
Authors | McTigue, M. / Deng, Y.-L. / Liu, W. / Brooun, A. / Stewart, A. | ||||||
Citation | Journal: N.Engl.J.Med. / Year: 2016 Title: Resensitization to Crizotinib by the Lorlatinib Alk Resistance Mutation L1198F. Authors: Shaw, A.T. / Friboulet, L. / Leshchiner, I. / Gainor, J.F. / Bergqvist, S. / Brooun, A. / Burke, B.J. / Deng, Y. / Liu, W. / Dardaei, L. / Frias, R.L. / Schultz, K.R. / Logan, J. / James, L. ...Authors: Shaw, A.T. / Friboulet, L. / Leshchiner, I. / Gainor, J.F. / Bergqvist, S. / Brooun, A. / Burke, B.J. / Deng, Y. / Liu, W. / Dardaei, L. / Frias, R.L. / Schultz, K.R. / Logan, J. / James, L.P. / Smeal, T. / Timofeevski, S. / Katayama, R. / Iafrate, A.J. / Le, L. / Mctigue, M. / Getz, G. / Johnson, T.W. / Engelman, J.A. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5aa9.cif.gz | 77.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5aa9.ent.gz | 57.4 KB | Display | PDB format |
PDBx/mmJSON format | 5aa9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/aa/5aa9 ftp://data.pdbj.org/pub/pdb/validation_reports/aa/5aa9 | HTTPS FTP |
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-Related structure data
Related structure data | 5a9uC 5aa8C 5aaaC 5aabC 5aacC 4cljS C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 36943.371 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, UNP RESIDUES 1093-1411 / Mutation: YES Source method: isolated from a genetically manipulated source Details: NON-PHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) References: UniProt: Q9UM73, receptor protein-tyrosine kinase | ||
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#2: Chemical | ChemComp-5P8 / ( | ||
#3: Water | ChemComp-HOH / | ||
Compound details | ENGINEEREDSequence details | RESIDUES 1093-1411, CONTAINING MUTATION L1198F, OF HUMAN ANAPLASTIC LYMPHOMA KINASE PLUS AN ...RESIDUES 1093-1411, CONTAINING | |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.1 Å3/Da / Density % sol: 41 % / Description: NONE |
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Crystal grow | Temperature: 286 K / Method: vapor diffusion, hanging drop / pH: 8 Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. 2 MICROLITERS OF PURIFIED PROTEIN SOLUTION (11-15 MG/ML) CONTAINING INHIBITOR COMPOUND AT A 2X STOICHIOMETRY OF INHIBITOR TO PROTEIN WERE ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. 2 MICROLITERS OF PURIFIED PROTEIN SOLUTION (11-15 MG/ML) CONTAINING INHIBITOR COMPOUND AT A 2X STOICHIOMETRY OF INHIBITOR TO PROTEIN WERE COMBINED WITH 2 MICROLITERS OF SOLUTIONS CONTAINING: 0.2 M LITHIUM SULFATE, 17-21% PEG3350 AND 0.1M TRIS PH 7.6-8.5. |
-Data collection
Diffraction | Mean temperature: 87 K |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 0.9795 |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 14, 2015 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9795 Å / Relative weight: 1 |
Reflection | Resolution: 1.93→57.18 Å / Num. obs: 23916 / % possible obs: 98.7 % / Observed criterion σ(I): 1 / Redundancy: 6.1 % / Biso Wilson estimate: 25.7 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 14.8 |
Reflection shell | Resolution: 1.93→2.11 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 3.2 / % possible all: 95.3 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 4CLJ Resolution: 1.93→52.52 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 1242060.23 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
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Solvent computation | Solvent model: FLAT MODEL / Bsol: 52.879 Å2 / ksol: 0.372366 e/Å3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 37 Å2
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Refine analyze |
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Refinement step | Cycle: LAST / Resolution: 1.93→52.52 Å
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Refine LS restraints |
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Refine LS restraints NCS | NCS model details: NONE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LS refinement shell | Resolution: 1.77→1.88 Å / Total num. of bins used: 6 /
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Xplor file |
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