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

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Basic information

Entry
Database: PDB / ID: 4mha
TitleCrystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1817
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-4MH / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsZhang, W. / Mciver, A. / Stashko, M.A. / Deryckere, D. / Branchford, B.R. / Hunter, D. / Kireev, D.B. / Miley, D.B.M. / Norris-Drouin, J. / Stewart, W.M. ...Zhang, W. / Mciver, A. / Stashko, M.A. / Deryckere, D. / Branchford, B.R. / Hunter, D. / Kireev, D.B. / Miley, D.B.M. / Norris-Drouin, J. / Stewart, W.M. / Lee, M. / Sather, S. / Zhou, Y. / Dipaola, J.A. / Machius, M. / Janzen, W.P. / Earp, H.S. / Graham, D.K. / Frye, S. / Wang, X.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
Authors: Zhang, W. / McIver, A.L. / Stashko, M.A. / DeRyckere, D. / Branchford, B.R. / Hunter, D. / Kireev, D. / Miley, M.J. / Norris-Drouin, J. / Stewart, W.M. / Lee, M. / Sather, S. / Zhou, Y. / Di ...Authors: Zhang, W. / McIver, A.L. / Stashko, M.A. / DeRyckere, D. / Branchford, B.R. / Hunter, D. / Kireev, D. / Miley, M.J. / Norris-Drouin, J. / Stewart, W.M. / Lee, M. / Sather, S. / Zhou, Y. / Di Paola, J.A. / Machius, M. / Janzen, W.P. / Earp, H.S. / Graham, D.K. / Frye, S.V. / Wang, X.
History
DepositionAug 29, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 21, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Revision 1.2Sep 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_asym_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_asym_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_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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)72,96911
Polymers71,7792
Non-polymers1,1909
Water41423
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4725
Polymers35,8891
Non-polymers5834
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4976
Polymers35,8891
Non-polymers6075
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.142, 91.460, 69.932
Angle α, β, γ (deg.)90.00, 100.23, 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.: 6 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-4MH / 2-(butylamino)-4-[(trans-4-hydroxycyclohexyl)amino]-N-(4-sulfamoylbenzyl)pyrimidine-5-carboxamide


Mass: 476.592 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H32N6O4S
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.24 Å3/Da / Density % sol: 45.15 %
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, 500mM sodium chloride, 2mM 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, 500mM sodium chloride, 2mM 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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 8, 2012
RadiationMonochromator: double-crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.59→40.07 Å / Num. all: 19608 / Num. obs: 19608 / % possible obs: 99.7 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 4.2 % / Biso Wilson estimate: 34.3 Å2 / Rmerge(I) obs: 0.117 / Net I/σ(I): 11.8
Reflection shellResolution: 2.59→2.61 Å / Redundancy: 4 % / Rmerge(I) obs: 0.711 / Mean I/σ(I) obs: 2 / Num. unique all: 483 / % possible all: 97.4

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Processing

Software
NameVersionClassification
PHASERphasing
PHENIX(phenix.refine: dev_1468)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3TCP

3tcp


Resolution: 2.59→40.066 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 31.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2939 1686 10 %random
Rwork0.2412 ---
obs0.2465 16853 84.91 %-
all-19608 --
Solvent computationShrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.59→40.066 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4038 0 73 23 4134
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024202
X-RAY DIFFRACTIONf_angle_d0.4775681
X-RAY DIFFRACTIONf_dihedral_angle_d9.081598
X-RAY DIFFRACTIONf_chiral_restr0.022633
X-RAY DIFFRACTIONf_plane_restr0.002708
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.59-2.66450.365670.2608601X-RAY DIFFRACTION41
2.6645-2.75040.2978970.2681878X-RAY DIFFRACTION59
2.7504-2.84870.34381110.2798994X-RAY DIFFRACTION67
2.8487-2.96270.3161250.28151125X-RAY DIFFRACTION77
2.9627-3.09750.31971390.28071252X-RAY DIFFRACTION85
3.0975-3.26080.30241540.28191388X-RAY DIFFRACTION92
3.2608-3.4650.35011590.25911438X-RAY DIFFRACTION98
3.465-3.73230.3211660.2351494X-RAY DIFFRACTION100
3.7323-4.10760.2891650.21811479X-RAY DIFFRACTION100
4.1076-4.70120.26141660.20981491X-RAY DIFFRACTION100
4.7012-5.91990.27811660.23051497X-RAY DIFFRACTION100
5.9199-40.0660.25131710.23131530X-RAY DIFFRACTION100

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