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- PDB-4uxl: Structure of Human ROS1 Kinase Domain in Complex with PF-06463922 -

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Basic information

Entry
Database: PDB / ID: 4uxl
TitleStructure of Human ROS1 Kinase Domain in Complex with PF-06463922
ComponentsPROTO-ONCOGENE TYROSINE-PROTEIN KINASE ROS
KeywordsTRANSFERASE / INHIBITOR / ROS
Function / homology
Function and homology information


columnar/cuboidal epithelial cell development / regulation of TOR signaling / transmembrane receptor protein tyrosine kinase activity / regulation of ERK1 and ERK2 cascade / regulation of cell growth / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / spermatogenesis / protein phosphatase binding / protein tyrosine kinase activity ...columnar/cuboidal epithelial cell development / regulation of TOR signaling / transmembrane receptor protein tyrosine kinase activity / regulation of ERK1 and ERK2 cascade / regulation of cell growth / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / spermatogenesis / protein phosphatase binding / protein tyrosine kinase activity / cell differentiation / receptor complex / protein phosphorylation / ATP binding / membrane / plasma membrane
Similarity search - Function
LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Tyrosine-protein kinase, receptor class II, conserved site / Six-bladed beta-propeller, TolB-like / Receptor tyrosine kinase class II signature. / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily ...LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Tyrosine-protein kinase, receptor class II, conserved site / Six-bladed beta-propeller, TolB-like / Receptor tyrosine kinase class II signature. / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-5P8 / Proto-oncogene tyrosine-protein kinase ROS
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsMcTigue, M. / Deng, Y. / Liu, W. / Brooun, A. / Stewart, A.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2015
Title: Pf-06463922 is a Potent and Selective Next-Generation Ros1/Alk Inhibitor Capable of Blocking Crizotinib-Resistant Ros1 Mutations.
Authors: Zou, H.Y. / Li, Q. / Engstrom, L.D. / West, M. / Appleman, V. / Wong, K.A. / Mctigue, M. / Deng, Y. / Liu, W. / Brooun, A. / Timofeevski, S. / Mcdonnell, S.R.P. / Jiang, P. / Falk, M.D. / ...Authors: Zou, H.Y. / Li, Q. / Engstrom, L.D. / West, M. / Appleman, V. / Wong, K.A. / Mctigue, M. / Deng, Y. / Liu, W. / Brooun, A. / Timofeevski, S. / Mcdonnell, S.R.P. / Jiang, P. / Falk, M.D. / Lappin, P.B. / Affolter, T. / Nichols, T. / Hu, W. / Lam, J. / Johnson, T.W. / Smeal, T. / Charest, A. / Fantin, V.R.
History
DepositionAug 25, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2015Group: Database references
Revision 1.2Apr 15, 2015Group: Database references
Revision 1.3Apr 24, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval
Revision 1.4May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp
Revision 1.5Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / software / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _software.name / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ROS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4212
Polymers37,0141
Non-polymers4061
Water2,450136
1
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ROS
hetero molecules

A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ROS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,8424
Polymers74,0292
Non-polymers8132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_655-x+1,-y,z1
Buried area3830 Å2
ΔGint-20.3 kcal/mol
Surface area26520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.844, 105.844, 49.843
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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Components

#1: Protein PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ROS / PROTO-ONCOGENE C-ROS / PROTO-ONCOGENE C-ROS-1 / RECEPTOR TYROSINE KINASE C-ROS ONCOGENE 1 / C-ROS ...PROTO-ONCOGENE C-ROS / PROTO-ONCOGENE C-ROS-1 / RECEPTOR TYROSINE KINASE C-ROS ONCOGENE 1 / C-ROS RECEPTOR TYROSINE KINASE


Mass: 37014.488 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP RESIDUES 1934-2232
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P08922, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5P8 / (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 / Lorlatinib


Mass: 406.413 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19FN6O2 / Comment: anticancer, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 136 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16, 17-TETRAHYDRO-2H-8,4-(METHENO) ...(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) (UNL): HET IS THE SAME AS 5P8 IN ENTRY 4CLJ

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.7 Å3/Da / Density % sol: 55 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: CRYSTALS WERE OBTAINED BY THE HANGING DROP VAPOR DIFFUSION METHOD AT 13 DEGREES C BY MIXING 1.5 MICROLITERS OF SOLUTION CONTAINING A 1:3 MOLAR RATIO OF PHOSPHORYLATED ROS1 KD (12.2MG/ML) TO ...Details: CRYSTALS WERE OBTAINED BY THE HANGING DROP VAPOR DIFFUSION METHOD AT 13 DEGREES C BY MIXING 1.5 MICROLITERS OF SOLUTION CONTAINING A 1:3 MOLAR RATIO OF PHOSPHORYLATED ROS1 KD (12.2MG/ML) TO PF-06463922 AND 1.5 MICROLITERS OF RESERVOIR SOLUTION CONTAINING 25% (W/V) PEG 3350, 0.6M POTASSIUM THIOCYANATE AND 0.1M SODIUM CITRATE TRIBASIC DIHYDRATE, PH5.6. CRYSTALS WERE FLASH-FROZEN IN LIQUID NITROGEN AFTER TRANSFER TO 2 MICROLITERS OF RESERVOIR SOLUTION CONTAINING 25% (V/V) GLYCEROL AS A CRYOPROTECTANT.

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.21→91.66 Å / Num. obs: 15684 / % possible obs: 97.1 % / Observed criterion σ(I): 2 / Redundancy: 6.7 % / Biso Wilson estimate: 41.4 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 27
Reflection shellResolution: 2.21→2.33 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.8 / % possible all: 62.1

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Processing

Software
NameVersionClassification
CNS2005refinement
autoPROCdata reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3ZBF

3zbf


Resolution: 2.4→91.66 Å / Rfactor Rfree error: 0.014 / Data cutoff high absF: 1439110.98 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.281 379 3 %RANDOM
Rwork0.211 ---
obs0.211 12648 100 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 55.3806 Å2 / ksol: 0.360053 e/Å3
Displacement parametersBiso mean: 50.4 Å2
Baniso -1Baniso -2Baniso -3
1--5.98 Å22.43 Å20 Å2
2---5.98 Å20 Å2
3---11.97 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.28 Å0.17 Å
Refinement stepCycle: LAST / Resolution: 2.4→91.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2310 0 30 136 2476
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d21.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.661.5
X-RAY DIFFRACTIONc_mcangle_it2.822
X-RAY DIFFRACTIONc_scbond_it2.132
X-RAY DIFFRACTIONc_scangle_it3.112.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.046 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.37 65 3.1 %
Rwork0.241 2024 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5UNL.PARAMUNL.TOP

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