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- PDB-6i99: Bone Marrow Tyrosine Kinase in Chromosome X in complex with a new... -

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Basic information

Entry
Database: PDB / ID: 6i99
TitleBone Marrow Tyrosine Kinase in Chromosome X in complex with a newly designed covalent inhibitor JS24
ComponentsCytoplasmic tyrosine-protein kinase BMX
KeywordsCYTOSOLIC PROTEIN / Cytoplasmic tyrosine-kinase BMX / Homo Sapiens
Function / homology
Function and homology information


phosphatidylinositol biosynthetic process / Apoptotic cleavage of cellular proteins / mesoderm development / Synthesis of PIPs at the plasma membrane / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / ruffle membrane / protein tyrosine kinase activity / adaptive immune response ...phosphatidylinositol biosynthetic process / Apoptotic cleavage of cellular proteins / mesoderm development / Synthesis of PIPs at the plasma membrane / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / ruffle membrane / protein tyrosine kinase activity / adaptive immune response / protein autophosphorylation / cell adhesion / intracellular signal transduction / protein phosphorylation / apoptotic process / signal transduction / nucleoplasm / ATP binding / metal ion binding / plasma membrane / cytosol
Similarity search - Function
BMX, SH2 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH2 domain ...BMX, SH2 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / 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. / 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-H88 / Cytoplasmic tyrosine-protein kinase BMX
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.001 Å
AuthorsSousa, B.B. / Matias, P.M. / Marques, M.C. / Seixas, J.D. / Bernardes, G.J.L.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
European Commission702428
Royal Society676832 United Kingdom
European Commission675007
Citation
Journal: Chem.Biol. / Year: 2020
Title: Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors
Authors: Seixas, J.D. / Sousa, B.B. / Marques, M.C. / Guerreiro, A. / Traquete, R. / Rodrigues, T. / Albuquerque, I.S. / Sousa, M.F.Q. / Lemos, A.R. / Sousa, P.M.F. / Bandeiras, T.M. / Wu, D. / ...Authors: Seixas, J.D. / Sousa, B.B. / Marques, M.C. / Guerreiro, A. / Traquete, R. / Rodrigues, T. / Albuquerque, I.S. / Sousa, M.F.Q. / Lemos, A.R. / Sousa, P.M.F. / Bandeiras, T.M. / Wu, D. / Doyle, S.K. / Robinson, C.V. / Koehler, A.N. / Corzana, F. / Matias, P.M. / Bernardes, G.J.L.
#1: Journal: Chemrxiv / Year: 2020
Title: Rationally Designed Potent BMX Inhibitors Reveals Mode of Covalent Binding at the Atomic Level
Authors: Seixas, J.D. / Sousa, B.B. / Marques, M.C. / Guerreiro, A. / Traquete, R. / Rodrigues, T. / Albuquerque, I.S. / Sousa, M.F.Q. / Lemos, A.R. / Sousa, P.M.F. / Bandeiras, T.M. / Wu, D. / ...Authors: Seixas, J.D. / Sousa, B.B. / Marques, M.C. / Guerreiro, A. / Traquete, R. / Rodrigues, T. / Albuquerque, I.S. / Sousa, M.F.Q. / Lemos, A.R. / Sousa, P.M.F. / Bandeiras, T.M. / Wu, D. / Doyle, S.K. / Robinson, C.V. / Koehler, A.N. / Corzana, F. / Matias, P.M. / Bernardes, G.J.L.
History
DepositionNov 22, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model
Item: _citation.journal_id_ISSN / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytoplasmic tyrosine-protein kinase BMX
B: Cytoplasmic tyrosine-protein kinase BMX
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,2144
Polymers65,1292
Non-polymers1,0852
Water2,270126
1
A: Cytoplasmic tyrosine-protein kinase BMX
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1072
Polymers32,5641
Non-polymers5431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytoplasmic tyrosine-protein kinase BMX
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1072
Polymers32,5641
Non-polymers5431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.714, 63.290, 74.962
Angle α, β, γ (deg.)90.00, 104.55, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Cytoplasmic tyrosine-protein kinase BMX / Bone marrow tyrosine kinase gene in chromosome X protein / Epithelial and endothelial tyrosine ...Bone marrow tyrosine kinase gene in chromosome X protein / Epithelial and endothelial tyrosine kinase / ETK / NTK38


Mass: 32564.414 Da / Num. of mol.: 2 / Mutation: Q432K, Q620E, Q611M, D617T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: Hematopoietic, endothelial, metastatic carcinoma / Gene: BMX / Variant: 2 / Plasmid: pFastBac1 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P51813, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-H88 / ~{N}-[2-methyl-5-[8-[4-(methylsulfonylamino)phenyl]-2-oxidanylidene-benzo[h][1,6]naphthyridin-1-yl]phenyl]-3-oxidanyl-propanamide


Mass: 542.606 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H26N4O5S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 126 / 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: 2.35 Å3/Da / Density % sol: 50.1 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: imidazole-malate, PEG 600 / PH range: 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Sep 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.98→72.6 Å / Num. obs: 23531 / % possible obs: 87.6 % / Redundancy: 4.2 % / Biso Wilson estimate: 23.6 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.181 / Rpim(I) all: 0.101 / Net I/σ(I): 6.1
Reflection shellResolution: 1.98→2.24 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1161 / CC1/2: 0.586 / Rpim(I) all: 0.489 / % possible all: 51.7

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SXS

3sxs


Resolution: 2.001→72.559 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / Phase error: 31.26
Details: NCS used between chain A and chain B TLS refinement of anisotropic ADPs - 4 non-equivalent rigid bodies were defined per protein chain. Hydrogen atoms were included in calculated positions.
RfactorNum. reflection% reflectionSelection details
Rfree0.2586 1184 5.04 %Random 5% selection
Rwork0.2321 ---
obs0.2335 23504 57.3 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Bsol: -2.2119 Å2 / ksol: 0.9549 e/Å3
Displacement parametersBiso mean: 23.6 Å2
Refinement stepCycle: LAST / Resolution: 2.001→72.559 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4308 0 76 126 4510
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024506
X-RAY DIFFRACTIONf_angle_d0.6036090
X-RAY DIFFRACTIONf_dihedral_angle_d11.282643
X-RAY DIFFRACTIONf_chiral_restr0.041631
X-RAY DIFFRACTIONf_plane_restr0.003756
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.001-2.09170.446130.3296198X-RAY DIFFRACTION4
2.0917-2.2020.2674260.3012558X-RAY DIFFRACTION11
2.202-2.33990.3991780.30531342X-RAY DIFFRACTION28
2.3399-2.52060.29441390.2962384X-RAY DIFFRACTION50
2.5206-2.77430.3181770.2843708X-RAY DIFFRACTION76
2.7743-3.17570.27762250.26094771X-RAY DIFFRACTION98
3.1757-4.0010.25962420.21344702X-RAY DIFFRACTION96
4.001-72.5590.21182840.19264657X-RAY DIFFRACTION94
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)
11.7889-0.42130.54831.2474-0.33631.2201-0.1280.2951-0.0835-0.12550.0498-0.00150.0447-0.011-0.00620.2-0.015-0.03580.3334-0.02340.134210.2146-18.329910.0771
21.5711-0.30090.69090.70640.02781.7043-0.09960.043-0.05640.027-0.0172-0.0375-0.0480.121-0.00170.1168-0.0127-0.02390.18270.00180.09449.5551-10.368222.6104
31.3236-0.19990.62060.53350.06241.01670.0607-0.1406-0.02080.0659-0.0447-0.05050.1659-0.1949-0.06990.1030.0035-0.07790.28960.05110.0547-0.9926-12.735135.0708
40.2362-0.10340.05090.396-0.1410.76020.015-0.18190.08550.2138-0.077500.0988-0.0451-0.26010.1388-0.0022-0.05060.1909-0.10750.05356.222-3.466442.5483
51.56910.25-0.13720.239-0.04320.3256-0.0791-0.14620.0590.14030.0255-0.0344-0.0024-0.1101-0.02470.08580.0416-0.06370.2663-0.02690.0547-25.04-19.351920.7943
61.87120.6949-0.13631.1325-0.56351.66840.0214-0.0798-0.17490.1872-0.04140.09910.0419-0.0482-0.03740.1842-0.00590.00320.1654-0.02530.1145-29.7101-11.61438.4207
70.26890.0097-0.03330.24350.02920.89930.0664-0.09810.02260.0502-0.0452-0.0139-0.1912-0.0046-0.00050.1287-0.0352-0.00390.22160.01440.0509-19.2233-12.12595.0188
80.21320.09460.03940.2039-0.22830.3723-0.02560.1639-0.0473-0.1023-0.0345-0.06360.10610.1947-0.16410.05910.02270.020.2147-0.05370.0396-20.7347-10.8418-9.6253
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 406 through 453 )
2X-RAY DIFFRACTION2chain 'A' and (resid 454 through 549 )
3X-RAY DIFFRACTION3chain 'A' and (resid 550 through 626 )
4X-RAY DIFFRACTION4chain 'A' and (resid 627 through 671 )
5X-RAY DIFFRACTION5chain 'B' and (resid 411 through 466 )
6X-RAY DIFFRACTION6chain 'B' and (resid 467 through 530 )
7X-RAY DIFFRACTION7chain 'B' and (resid 531 through 575 )
8X-RAY DIFFRACTION8chain 'B' and (resid 576 through 671 )

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