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- PDB-5val: BRAF in Complex with N-(3-(tert-butyl)phenyl)-4-methyl-3-(6-morph... -

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Basic information

Entry
Database: PDB / ID: 5val
TitleBRAF in Complex with N-(3-(tert-butyl)phenyl)-4-methyl-3-(6-morpholinopyrimidin-4-yl)benzamide
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE inhibitor / BRAF Serine/threonine-protein kinase B-raf / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / positive regulation of axonogenesis / Frs2-mediated activation / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / thyroid gland development / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / long-term synaptic potentiation / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / presynapse / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / neuron projection / protein phosphorylation / intracellular membrane-bounded organelle / protein serine kinase activity / protein serine/threonine kinase activity / calcium ion binding / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / mitochondrion / ATP binding / identical protein binding / nucleus / plasma membrane / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-92D / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.26 Å
AuthorsMamo, M. / Appleton, B.A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF ...Title: Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.
Authors: Nishiguchi, G.A. / Rico, A. / Tanner, H. / Aversa, R.J. / Taft, B.R. / Subramanian, S. / Setti, L. / Burger, M.T. / Wan, L. / Tamez, V. / Smith, A. / Lou, Y. / Barsanti, P.A. / Appleton, B.A. ...Authors: Nishiguchi, G.A. / Rico, A. / Tanner, H. / Aversa, R.J. / Taft, B.R. / Subramanian, S. / Setti, L. / Burger, M.T. / Wan, L. / Tamez, V. / Smith, A. / Lou, Y. / Barsanti, P.A. / Appleton, B.A. / Mamo, M. / Tandeske, L. / Dix, I. / Tellew, J.E. / Huang, S. / Mathews Griner, L.A. / Cooke, V.G. / Van Abbema, A. / Merritt, H. / Ma, S. / Gampa, K. / Feng, F. / Yuan, J. / Wang, Y. / Haling, J.R. / Vaziri, S. / Hekmat-Nejad, M. / Jansen, J.M. / Polyakov, V. / Zang, R. / Sethuraman, V. / Amiri, P. / Singh, M. / Lees, E. / Shao, W. / Stuart, D.D. / Dillon, M.P. / Ramurthy, S.
History
DepositionMar 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)64,6894
Polymers63,8282
Non-polymers8612
Water4,900272
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3442
Polymers31,9141
Non-polymers4311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3442
Polymers31,9141
Non-polymers4311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.121, 94.121, 163.537
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 31913.881 Da / Num. of mol.: 2 / Fragment: UNP residues 445-723
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: unidentified baculovirus
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-92D / N-(3-tert-butylphenyl)-4-methyl-3-[6-(morpholin-4-yl)pyrimidin-4-yl]benzamide


Mass: 430.542 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30N4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 272 / 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: 2.84 Å3/Da / Density % sol: 56.65 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.4 / Details: 100 mM Tris ph 8.4, 12% PEG8000, and 100mM NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 27, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.26→47.06 Å / Num. obs: 33857 / % possible obs: 95.6 % / Redundancy: 8.8 % / Biso Wilson estimate: 40.2 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.05 / Rrim(I) all: 0.148 / Net I/σ(I): 14.3
Reflection shell

Diffraction-ID: 1 / Resolution: 2.26→2.38 Å

Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
8.90.140.7730.3331.00199.5
7.90.0370.9980.0140.03999.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.27data scaling
Cootmodel building
BUSTER2.11.6refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→47.06 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.924 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.215 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.23 / SU Rfree Blow DPI: 0.183 / SU Rfree Cruickshank DPI: 0.179
RfactorNum. reflection% reflectionSelection details
Rfree0.217 1724 5.12 %RANDOM
Rwork0.181 ---
obs0.183 33658 95.6 %-
Displacement parametersBiso max: 138.67 Å2 / Biso mean: 38.11 Å2 / Biso min: 13.52 Å2
Baniso -1Baniso -2Baniso -3
1--1.4841 Å20 Å20 Å2
2---1.4841 Å20 Å2
3---2.9681 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 2.26→47.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4035 0 64 272 4371
Biso mean--30.49 42.08 -
Num. residues----508
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1462SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes91HARMONIC2
X-RAY DIFFRACTIONt_gen_planes645HARMONIC5
X-RAY DIFFRACTIONt_it4191HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion538SEMIHARMONIC5
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_contact4990SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4191HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5664HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion15.62
LS refinement shellResolution: 2.26→2.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.232 166 5.51 %
Rwork0.197 2847 -
all0.198 3013 -
obs--100 %
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)
13.20.7447-0.01290.6061.22531.4462-0.0680.30050.1-0.1847-0.08230.2366-0.2341-0.08250.15030.0285-0.0094-0.0352-0.04230.0267-0.0463-20.113446.4119-15.6343
20.90561.75320.3581.7940.09580.4913-0.0273-0.21060.2869-0.0442-0.08740.0669-0.3766-0.00740.11470.1708-0.04920.0327-0.096-0.0777-0.0406-15.408553.5913-4.7506
32.2473-0.3882-1.68611.01050.3912.3378-0.31690.1229-0.2222-0.00070.11360.27520.1798-0.13380.2033-0.0811-0.00710.0285-0.0574-0.0150.0095-25.284437.7841-0.2292
40.7677-0.1569-0.03660-0.20870.0737-0.01050.06930.14990.0192-0.01360.0092-0.0246-0.03950.024-0.03570.05230.0837-0.03860.00650.0283-35.378248.68038.7661
54.6364-2.2682-2.3690.88090.80011.1428-0.3395-0.3573-0.24060.2860.16140.2510.15010.11940.1781-0.03220.04670.0916-0.05270.0564-0.0372-35.693144.661615.7746
60-2.89070.71590.0855-2.17010.0059-0.0314-0.0656-0.30420.13990.0357-0.0490.1721-0.0145-0.00440.05760.1520.152-0.00320.0863-0.0622-23.878430.122317.4999
71.8554-0.54291.03331.52291.12651.1393-0.0285-0.3218-0.28850.0736-0.0631-0.06080.36140.46170.09150.03660.11270.0320.00320.0603-0.0709-3.59427.30717.6008
81.1731-0.7726-0.55711.4073-1.68741.92090.0023-0.0522-0.05590.3347-0.1658-0.01420.26480.40490.1635-0.05960.0745-0.01770.0480.0366-0.0566-0.696628.10087.8549
90.67032.20940.76541.4749-1.52360.2887-0.0235-0.11510.0456-0.1495-0.0228-0.14740.11970.41610.0462-0.09240.0160.04550.2191-0.0571-0.15165.291933.0595-2.4333
100.9497-0.014-0.46521.75381.06941.6948-0.0494-0.0403-0.19620.0911-0.05340.09650.1627-0.04430.1028-0.04870.00680.0567-0.0393-0.01040.0024-10.329123.2064-8.4778
1100.80150.19673.44760.34513.20340.0029-0.0266-0.04280.24260.0655-0.03060.25540.0062-0.06840.00960.02030.0249-0.0532-0.0331-0.0021-9.434221.9451-7.0397
121.6839-1.9292-0.45143.84670.97870.87240.03530.1039-0.1582-0.1454-0.11490.1275-0.0098-0.08710.0797-0.0587-0.01270.0362-0.0176-0.0827-0.0329-2.177513.4001-23.6134
130.5493-2.54062.48160-2.27242.16380.01150.1250.04-0.06160.03840.3077-0.1095-0.0876-0.04990.02640.0421-0.0169-0.0274-0.0867-0.0413-17.52125.1103-26.5782
140.1427-1.16380.44530.7216-0.47840.37340.0089-0.0248-0.0301-0.02450.02290.03590.008-0.0179-0.03170.0468-0.0253-0.0147-0.01610.0123-0.0269-23.091143.6048-5.035
150.7819-1.15260.98870.7306-0.22050.5875-0.00670.0139-0.0638-0.02240.07310.0024-0.00210.0556-0.06640.01020.0286-0.0207-0.0082-0.0068-0.0007-4.695225.0539-3.1275
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|449 - A|491 }A449 - 491
2X-RAY DIFFRACTION2{ A|492 - A|507 }A492 - 507
3X-RAY DIFFRACTION3{ A|508 - A|596 }A508 - 596
4X-RAY DIFFRACTION4{ A|616 - A|621 }A616 - 621
5X-RAY DIFFRACTION5{ A|622 - A|706 }A622 - 706
6X-RAY DIFFRACTION6{ A|707 - A|720 }A707 - 720
7X-RAY DIFFRACTION7{ B|449 - B|475 }B449 - 475
8X-RAY DIFFRACTION8{ B|476 - B|491 }B476 - 491
9X-RAY DIFFRACTION9{ B|492 - B|507 }B492 - 507
10X-RAY DIFFRACTION10{ B|508 - B|587 }B508 - 587
11X-RAY DIFFRACTION11{ B|588 - B|597 }B588 - 597
12X-RAY DIFFRACTION12{ B|615 - B|706 }B615 - 706
13X-RAY DIFFRACTION13{ B|707 - B|721 }B707 - 721
14X-RAY DIFFRACTION14{ A|801 - A|801 }A801
15X-RAY DIFFRACTION15{ B|801 - B|801 }B801

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