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- PDB-6xlo: Crystal structure of bRaf in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6xlo
TitleCrystal structure of bRaf in complex with inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homologyIODIDE ION / Chem-V5J
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.493 Å
AuthorsYin, J. / Eigenbrot, C. / 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
DepositionJun 28, 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: Serine/threonine-protein kinase B-raf
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,7035
Polymers65,6652
Non-polymers1,0383
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2430 Å2
ΔGint-6 kcal/mol
Surface area23430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.059, 104.779, 60.258
Angle α, β, γ (deg.)90.000, 109.690, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Serine/threonine-protein kinase B-raf


Mass: 32832.621 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF / Production host: Escherichia coli (E. coli)
#2: Chemical ChemComp-V5J / 3-(2-cyanopropan-2-yl)-N-[2-fluoro-4-methyl-5-(7-methyl-8-oxo-7,8-dihydropyrido[2,3-d]pyridazin-3-yl)phenyl]benzamide


Mass: 455.484 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H22FN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.18 Å3/Da / Density % sol: 43.46 %
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: Apr 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.49→56.73 Å / Num. obs: 19111 / % possible obs: 97.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 41.02 Å2 / CC1/2: 0.978 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.104 / Rrim(I) all: 0.193 / Net I/σ(I): 6.1
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
2.49-2.633.20.55875527040.6880.360.662.394.8
7.88-49.893.30.08420696280.9870.0550.111.597

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (20-MAY-2020)refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3C4C

3c4c


Resolution: 2.493→56.73 Å / Cor.coef. Fo:Fc: 0.861 / Cor.coef. Fo:Fc free: 0.823 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.73 / SU Rfree Blow DPI: 0.306 / SU Rfree Cruickshank DPI: 0.316
RfactorNum. reflection% reflectionSelection details
Rfree0.2673 866 4.54 %RANDOM
Rwork0.2351 ---
obs0.2366 19069 97.1 %-
Displacement parametersBiso max: 74.99 Å2 / Biso mean: 30.69 Å2 / Biso min: 6.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.6157 Å20 Å20.6171 Å2
2---1.2643 Å20 Å2
3---0.6487 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 2.493→56.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4074 0 69 87 4230
Biso mean--14.84 19.42 -
Num. residues----508
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1517SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes701HARMONIC5
X-RAY DIFFRACTIONt_it4236HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion532SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3295SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4236HARMONIC20.007
X-RAY DIFFRACTIONt_angle_deg5703HARMONIC20.86
X-RAY DIFFRACTIONt_omega_torsion2.64
X-RAY DIFFRACTIONt_other_torsion18.96
LS refinement shellResolution: 2.493→2.52 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.188 27 6.08 %
Rwork0.237 417 -
obs--83.27 %
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)
13.7291-1.14110.72612.9246-0.75991.9921-0.09310.12350.1373-0.04190.0687-0.0511-0.2156-0.03630.02430.1091-0.00250.06250.01960.0220.0491-6.0095-20.1022-17.031
23.7261-1.5933-0.62773.46271.19742.2432-0.11690.1476-0.2658-0.03540.07310.16350.2385-0.03890.04380.1095-0.038-0.03010.0391-0.01280.07872.4654-52.5451-17.498
30.0156-0.08080.38171.30730.06010.580.08440.08080.2708-0.07720.0541-0.16670.1151-0.0487-0.1384-0.1504-0.00780.05150.0044-0.0406-0.3014-2.0401-35.9635-13.1044
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A449 - 720
2X-RAY DIFFRACTION2{ B|* }B450 - 720
3X-RAY DIFFRACTION3{ S|* }B0

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