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- PDB-4m3q: Crystal structure of the catalytic domain of the proto-oncogene t... -

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Basic information

Entry
Database: PDB / ID: 4m3q
TitleCrystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1917
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TYROSINE KINASE / ACUTE LYMPHOBLASTIC LEUKEMIA / RATIONAL STRUCTURE-BASED DRUG DESIGN / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


negative regulation of leukocyte apoptotic process / negative regulation of lymphocyte activation / neutrophil clearance / natural killer cell differentiation / secretion by cell / negative regulation of cytokine production / vagina development / photoreceptor outer segment / positive regulation of phagocytosis / phagocytosis ...negative regulation of leukocyte apoptotic process / negative regulation of lymphocyte activation / neutrophil clearance / natural killer cell differentiation / secretion by cell / negative regulation of cytokine production / vagina development / photoreceptor outer segment / positive regulation of phagocytosis / phagocytosis / transmembrane receptor protein tyrosine kinase activity / substrate adhesion-dependent cell spreading / phosphatidylinositol 3-kinase/protein kinase B signal transduction / establishment of localization in cell / Cell surface interactions at the vascular wall / receptor protein-tyrosine kinase / platelet activation / cell surface receptor protein tyrosine kinase signaling pathway / cell migration / retina development in camera-type eye / cell-cell signaling / nervous system development / spermatogenesis / cell surface receptor signaling pathway / receptor complex / protein phosphorylation / extracellular space / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / 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 ...Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / 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. / Immunoglobulin subtype / Immunoglobulin / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / 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-24K / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.718 Å
AuthorsZhang, W. / Zhang, D. / Stashko, M.A. / DeRyckere, D. / Hunter, D. / Kireev, D.B. / Miley, M. / Cummings, C. / Lee, M. / Norris-Drouin, J. ...Zhang, W. / Zhang, D. / Stashko, M.A. / DeRyckere, D. / Hunter, D. / Kireev, D.B. / Miley, M. / Cummings, C. / Lee, M. / Norris-Drouin, J. / Stewart, W.M. / Sather, S. / Zhou, Y. / Kirkpatrick, G. / Machius, M. / Janzen, W.P. / Earp, H.S. / Graham, D.K. / Frye, S. / Wang, X.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors.
Authors: Zhang, W. / Zhang, D. / Stashko, M.A. / Deryckere, D. / Hunter, D. / Kireev, D. / Miley, M.J. / Cummings, C. / Lee, M. / Norris-Drouin, J. / Stewart, W.M. / Sather, S. / Zhou, Y. / ...Authors: Zhang, W. / Zhang, D. / Stashko, M.A. / Deryckere, D. / Hunter, D. / Kireev, D. / Miley, M.J. / Cummings, C. / Lee, M. / Norris-Drouin, J. / Stewart, W.M. / Sather, S. / Zhou, Y. / Kirkpatrick, G. / Machius, M. / Janzen, W.P. / Earp, H.S. / Graham, D.K. / Frye, S.V. / Wang, X.
History
DepositionAug 6, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_ref_seq_dif.details / _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: Tyrosine-protein kinase Mer
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,73412
Polymers71,7792
Non-polymers95510
Water1086
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3977
Polymers35,8891
Non-polymers5086
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3375
Polymers35,8891
Non-polymers4484
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.924, 91.120, 69.699
Angle α, β, γ (deg.)90.00, 99.81, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase Mer / Proto-oncogene c-Mer / Receptor tyrosine kinase MerTK


Mass: 35889.434 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 570-864
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MER, MERTK / Plasmid: PET28 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): ROSETTA BL21(DE3)PLYSS
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-24K / trans-4-{[2-(butylamino)-5-(pyridin-2-yl)pyrimidin-4-yl]amino}cyclohexanol


Mass: 341.451 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H27N5O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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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: 2.18 Å3/Da / Density % sol: 43.68 %
Crystal growTemperature: 288 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein: 32.5 mg/mL in 20 mM Tris pH 8.0, 500 mM sodium chloride, 2 mM beta-mercaptoethanol, incubated with inhibitor (2.5 mM final concentration) overnight, Mixed 1:1 with crystallization ...Details: Protein: 32.5 mg/mL in 20 mM Tris pH 8.0, 500 mM sodium chloride, 2 mM beta-mercaptoethanol, incubated with inhibitor (2.5 mM final concentration) overnight, Mixed 1:1 with crystallization solution (27-33% (v/v) Peg400, 200 mM magnesium chloride, 100 mM Tris pH 8.5), vapor diffusion, sitting drop, temperature 288K, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 0.97921 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 13, 2012
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97921 Å / Relative weight: 1
ReflectionResolution: 2.71→34.74 Å / Num. all: 16507 / Num. obs: 16507 / % possible obs: 97.5 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 4.1 % / Biso Wilson estimate: 32.27 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 11.6
Reflection shellResolution: 2.71→2.73 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 2.3 / Num. unique all: 422 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIXmodel building
PHENIX(phenix.refine: dev_1439)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3TCP

3tcp


Resolution: 2.718→34.74 Å / SU ML: 0.38 / σ(F): 1.33 / Phase error: 32.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2958 1420 10 %Random
Rwork0.243 ---
obs0.2483 14204 83.57 %-
all-16507 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.718→34.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3860 0 58 6 3924
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033993
X-RAY DIFFRACTIONf_angle_d0.6535387
X-RAY DIFFRACTIONf_dihedral_angle_d11.0471497
X-RAY DIFFRACTIONf_chiral_restr0.026608
X-RAY DIFFRACTIONf_plane_restr0.003663
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.718-2.8150.2763880.2276786X-RAY DIFFRACTION51
2.815-2.92770.33361030.239938X-RAY DIFFRACTION62
2.9277-3.06080.29251200.24831075X-RAY DIFFRACTION71
3.0608-3.22210.32621400.26571257X-RAY DIFFRACTION83
3.2221-3.42380.32661600.28211444X-RAY DIFFRACTION93
3.4238-3.68790.37281600.29791437X-RAY DIFFRACTION95
3.6879-4.05850.31491330.28111217X-RAY DIFFRACTION80
4.0585-4.64460.22831720.18631549X-RAY DIFFRACTION100
4.6446-5.84720.26431690.20941520X-RAY DIFFRACTION100
5.8472-34.740.28081750.22831561X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.3889-0.8195-1.00241.8514-0.1662.01730.1243-0.19580.35260.10280.0097-0.171-0.24750.3163-0.05250.2375-0.05210.00130.29220.01280.1246-9.159751.4036-13.9479
21.6338-0.6809-0.77280.8565-0.21730.8736-0.1205-0.01370.0690.22590.02820.357-0.22420.3114-0.26830.4705-0.19290.01340.2752-0.00750.2989-13.400248.3077-28.6872
32.26840.35871.25180.37370.34750.7613-0.3524-0.13160.19080.18030.0202-0.2172-0.41340.21230.190.2503-0.0417-0.09530.47130.07640.2149-0.713350.3123-15.2412
42.73840.7760.78273.7195-1.39910.97440.1996-0.30630.46330.74070.21160.5869-0.1583-0.453-0.14410.6154-0.09070.11070.29020.02030.3024-26.782534.3208-15.5801
52.96250.21740.3621.9569-0.06012.6640.39850.43230.5017-0.2956-0.22640.1509-0.40030.1615-0.06910.50160.0383-0.01010.22350.05790.313-19.416938.9283-29.3181
61.0377-0.31830.79693.5469-1.15852.93180.27990.0427-0.1757-0.1793-0.3143-0.46770.04220.55830.03140.42330.0090.04910.2791-0.00540.3612-14.135423.1613-30.9924
73.1523-0.5349-0.3213.9867-0.50611.9178-0.06240.4079-0.0874-0.10980.07720.30620.1488-0.421-0.08160.3769-0.0574-0.06040.2625-0.00030.2284-25.132526.6313-37.7821
81.526-0.3621-1.35682.4418-0.18781.31660.2923-0.2744-0.43680.09570.1176-0.00280.13110.40010.46320.52410.1229-0.19260.50570.09910.4625-6.0246-9.2718-13.754
95.44412.92951.75593.48062.88315.8397-0.51910.27510.0632-0.83760.9362-0.1318-0.05970.7562-0.28380.6613-0.0172-0.00020.2721-0.06290.3035-10.4151-5.3149-17.5564
102.6519-0.1154-0.71391.88860.19692.1597-0.0490.1653-0.3122-0.10320.0831-0.07210.06730.2171-0.0350.2413-0.0636-0.04450.1845-0.0090.2772-21.53062.4894-10.083
111.75770.2064-0.5562.56150.10212.10090.1131-0.0560.03920.2493-0.0559-0.2406-0.03530.1801-0.02550.1926-0.0293-0.02110.19870.0380.1609-23.754915.6301-1.739
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 578 through 619 )
2X-RAY DIFFRACTION2chain 'A' and (resid 620 through 651 )
3X-RAY DIFFRACTION3chain 'A' and (resid 652 through 672 )
4X-RAY DIFFRACTION4chain 'A' and (resid 673 through 696 )
5X-RAY DIFFRACTION5chain 'A' and (resid 697 through 763 )
6X-RAY DIFFRACTION6chain 'A' and (resid 764 through 814 )
7X-RAY DIFFRACTION7chain 'A' and (resid 815 through 861 )
8X-RAY DIFFRACTION8chain 'B' and (resid 577 through 594 )
9X-RAY DIFFRACTION9chain 'B' and (resid 600 through 620 )
10X-RAY DIFFRACTION10chain 'B' and (resid 621 through 716 )
11X-RAY DIFFRACTION11chain 'B' and (resid 717 through 861 )

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