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- PDB-7k0v: Crystal structure of bRaf in complex with inhibitor GNE-0749 -

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Basic information

Entry
Database: PDB / ID: 7k0v
TitleCrystal structure of bRaf in complex with inhibitor GNE-0749
ComponentsNon-specific serine/threonine protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


non-specific serine/threonine protein kinase / positive regulation of protein phosphorylation / protein phosphorylation / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / negative regulation of apoptotic process / signal transduction / ATP binding / cytosol
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-VQP / non-specific serine/threonine protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsYin, J. / Eigenbrot, C.E. / Wang, W.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3 H )-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.
Authors: Huestis, M.P. / Dela Cruz, D. / DiPasquale, A.G. / Durk, M.R. / Eigenbrot, C. / Gibbons, P. / Gobbi, A. / Hunsaker, T.L. / La, H. / Leung, D.H. / Liu, W. / Malek, S. / Merchant, M. / Moffat, ...Authors: Huestis, M.P. / Dela Cruz, D. / DiPasquale, A.G. / Durk, M.R. / Eigenbrot, C. / Gibbons, P. / Gobbi, A. / Hunsaker, T.L. / La, H. / Leung, D.H. / Liu, W. / Malek, S. / Merchant, M. / Moffat, J.G. / Muli, C.S. / Orr, C.J. / Parr, B.T. / Shanahan, F. / Sneeringer, C.J. / Wang, W. / Yen, I. / Yin, J. / Siu, M. / Rudolph, J.
History
DepositionSep 6, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 26, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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: Non-specific serine/threonine protein kinase
B: Non-specific serine/threonine protein kinase
C: Non-specific serine/threonine protein kinase
D: Non-specific serine/threonine protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,17510
Polymers131,3304
Non-polymers1,8456
Water7,819434
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8380 Å2
ΔGint-56 kcal/mol
Surface area47880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.254, 115.354, 119.390
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Non-specific serine/threonine protein kinase


Mass: 32832.621 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF / Production host: Escherichia coli (E. coli)
References: UniProt: H7C560, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-VQP / N-(3,3-dimethylbutyl)-N'-{2-fluoro-5-[(5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]-4-methylphenyl}urea


Mass: 443.490 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H27F2N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 434 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.29 Å3/Da / Density % sol: 46.23 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: 18% PEG 3350, and 0.2M Na Nitrate, and 0.1 M bis-Tris propane pH 6.5

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.93→49.27 Å / Num. obs: 60440 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.046 / Rrim(I) all: 0.12 / Net I/σ(I): 13.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.37-2.56.50.8254654771720.7670.3510.8982.4100
7.49-48.1260.0291045617340.9990.0130.03139.699.6

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.18.2-3874_finalrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3C4C

3c4c


Resolution: 1.93→49.27 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 27.96 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2304 2972 4.92 %
Rwork0.1844 57458 -
obs0.1867 60430 66.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 109.46 Å2 / Biso mean: 37.2805 Å2 / Biso min: 17.29 Å2
Refinement stepCycle: final / Resolution: 1.93→49.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8508 0 130 434 9072
Biso mean--26.47 36.51 -
Num. residues----1064
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.93-1.970.4971120.3385188
1.97-20.3153180.3015237
2-2.040.3695160.2771312
2.04-2.070.3027280.2937406
2.07-2.120.2911380.2848543
2.12-2.1635767
2.16-2.210.2698520.2593103825
2.21-2.270.2941930.2549180744
2.27-2.330.29791580.2546297173
2.33-2.40.3031930.2581375292
2.4-2.480.32192150.2377397198
2.48-2.560.28471830.2264128100
2.56-2.670.27762160.22084056100
2.67-2.790.29172040.22324118100
2.79-2.940.22992190.22674090100
2.94-3.120.24282190.21124100100
3.12-3.360.23951950.17984142100
3.36-3.70.22412070.16534133100
3.7-4.230.2092450.14184131100
4.23-5.330.15762190.12844181100
5.33-49.270.19852070.16264387100
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)
10.5601-0.058-0.35681.6243-0.92791.8079-0.02250.00960.039-0.07870.10090.1345-0.0213-0.08360.00240.1591-0.0113-0.02760.174-0.02980.163640.506-5.14-33.343
20.9786-0.2735-0.21612.37710.9361.96-0.0883-0.0161-0.0118-0.07450.1489-0.31910.191-0.04230.01520.1536-0.01380.03660.19720.00710.28552.758-1.245-33.363
31.29910.25650.30541.96840.48042.17330.01440.1070.0696-0.1459-0.00550.3096-0.0787-0.1486-0.00540.1256-0.0158-0.00360.17770.02340.219430.83729.419-45.483
40.9563-0.106-0.40961.9907-0.16741.93450.05450.07080.1677-0.15550.0499-0.1306-0.02020.18010.00280.1702-0.0223-0.01780.2388-0.0020.241114.915-35.221-43.929
50.00590.00620.04860.14530.03410.047200.00380.0343-0.0013-0.00450.0780.0284-0.0045-00.2205-0.0010.02020.2410.00520.242125.241-3.179-36.773
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 449:722 ) OR ( CHAIN A AND RESID 801:801 )A449 - 722
2X-RAY DIFFRACTION2( CHAIN B AND RESID 449:722 ) OR ( CHAIN B AND RESID 801:801 )B449 - 722
3X-RAY DIFFRACTION3( CHAIN C AND RESID 448:722 ) OR ( CHAIN C AND RESID 801:801 )C448 - 722
4X-RAY DIFFRACTION4( CHAIN D AND RESID 449:722 ) OR ( CHAIN D AND RESID 801:801 )D449 - 722
5X-RAY DIFFRACTION5( CHAIN A AND RESID 802:802 ) OR ( CHAIN B AND RESID 802:802 )A802
6X-RAY DIFFRACTION5( CHAIN A AND RESID 802:802 ) OR ( CHAIN B AND RESID 802:802 )B802

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