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- PDB-3c4c: B-Raf Kinase in Complex with PLX4720 -

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Basic information

Entry
Database: PDB / ID: 3c4c
TitleB-Raf Kinase in Complex with PLX4720
ComponentsB-Raf proto-oncogene serine/threonine-protein kinase
KeywordsTRANSFERASE / B-RAF / BRAF / RAF / PROTO-ONCOGENE / SERINE/THREONINE KINASE / ATP-binding / Cardiomyopathy / Cytoplasm / Disease mutation / Metal-binding / Nucleotide-binding / Phorbol-ester binding / Phosphoprotein / Polymorphism / Serine/threonine-protein kinase / Zinc / Zinc-finger
Function / homology
Function and homology information


trehalose metabolism in response to stress / Signalling to p38 via RIT and RIN / Gain-of-function MRAS complexes activate RAF signaling / SHOC2 M1731 mutant abolishes MRAS complex function / ARMS-mediated activation / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / MAP kinase kinase kinase activity ...trehalose metabolism in response to stress / Signalling to p38 via RIT and RIN / Gain-of-function MRAS complexes activate RAF signaling / SHOC2 M1731 mutant abolishes MRAS complex function / ARMS-mediated activation / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / MAP kinase kinase kinase activity / MAP kinase kinase activity / cellular response to calcium ion / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / animal organ morphogenesis / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling by moderate kinase activity BRAF mutants / Signaling downstream of RAS mutants / MAPK cascade / Signaling by BRAF and RAF1 fusions / scaffold protein binding / positive regulation of peptidyl-serine phosphorylation / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / intracellular membrane-bounded organelle / protein serine kinase activity / protein serine/threonine kinase activity / protein phosphorylation / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / ATP binding / identical protein binding / plasma membrane / nucleus / cytosol
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding domain / Ras-binding domain (RBD) profile. / Raf-like Ras-binding / 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 domain / Ras-binding domain (RBD) profile. / Raf-like Ras-binding / 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 / Ubiquitin-like domain superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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-324 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 Å
AuthorsZhang, K.Y.J. / Wang, W.
CitationJournal: Proc.Natl.Acad.Sci.Usa / Year: 2008
Title: Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
Authors: Tsai, J. / Lee, J.T. / Wang, W. / Zhang, J. / Cho, H. / Mamo, S. / Bremer, R. / Gillette, S. / Kong, J. / Haass, N.K. / Sproesser, K. / Li, L. / Smalley, K.S. / Fong, D. / Zhu, Y.L. / ...Authors: Tsai, J. / Lee, J.T. / Wang, W. / Zhang, J. / Cho, H. / Mamo, S. / Bremer, R. / Gillette, S. / Kong, J. / Haass, N.K. / Sproesser, K. / Li, L. / Smalley, K.S. / Fong, D. / Zhu, Y.L. / Marimuthu, A. / Nguyen, H. / Lam, B. / Liu, J. / Cheung, I. / Rice, J. / Suzuki, Y. / Luu, C. / Settachatgul, C. / Shellooe, R. / Cantwell, J. / Kim, S.H. / Schlessinger, J. / Zhang, K.Y. / West, B.L. / Powell, B. / Habets, G. / Zhang, C. / Ibrahim, P.N. / Hirth, P. / Artis, D.R. / Herlyn, M. / Bollag, G.
History
DepositionJan 29, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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 / _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

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Assembly

Deposited unit
A: B-Raf proto-oncogene serine/threonine-protein kinase
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5794
Polymers63,7512
Non-polymers8282
Water2,756153
1
A: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2892
Polymers31,8761
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2892
Polymers31,8761
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.574, 105.502, 110.150
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein B-Raf proto-oncogene serine/threonine-protein kinase / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 31875.529 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
Mutation: I543A, I544S, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)RIL
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-324 / N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide


Mass: 413.826 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H14ClF2N3O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 153 / 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: 47.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100mM BisTris at pH 6.0, 12.5% 2,5-hexanediol, and 12% PEG3350, VAPOR DIFFUSION, HANGING DROP, temperature 277.0K

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Data collection

DiffractionMean temperature: 295 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Apr 15, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.57→50 Å / Num. obs: 19778 / % possible obs: 99.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 4.6 % / Rsym value: 0.105 / Net I/σ(I): 4.9
Reflection shellResolution: 2.57→2.75 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 1.3 / Rsym value: 0.562 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.1.25refinement
Blu-Icedata collection
MOSFLMdata reduction
SCALAdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.57→50 Å / Cor.coef. Fo:Fc: 0.876 / Cor.coef. Fo:Fc free: 0.842 / SU B: 18.129 / SU ML: 0.369 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 1.14 / ESU R Free: 0.38 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30334 952 4.8 %RANDOM
Rwork0.25859 ---
obs0.26078 18805 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.647 Å2
Baniso -1Baniso -2Baniso -3
1-4.04 Å20 Å20 Å2
2---1.78 Å20 Å2
3----2.26 Å2
Refinement stepCycle: LAST / Resolution: 2.57→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4112 0 54 153 4319
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0214256
X-RAY DIFFRACTIONr_bond_other_d0.0020.023859
X-RAY DIFFRACTIONr_angle_refined_deg2.0591.9665743
X-RAY DIFFRACTIONr_angle_other_deg1.05238993
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.2665511
X-RAY DIFFRACTIONr_chiral_restr0.1760.2618
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024669
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02859
X-RAY DIFFRACTIONr_nbd_refined0.2420.21187
X-RAY DIFFRACTIONr_nbd_other0.2410.24827
X-RAY DIFFRACTIONr_nbtor_other0.0940.22551
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2660.2135
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1920.226
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2510.256
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2120.24
X-RAY DIFFRACTIONr_mcbond_it0.4921.52560
X-RAY DIFFRACTIONr_mcangle_it0.8224133
X-RAY DIFFRACTIONr_scbond_it1.35931696
X-RAY DIFFRACTIONr_scangle_it2.0534.51610
LS refinement shellResolution: 2.57→2.637 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.445 67
Rwork0.335 1369
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
1-0.2455-0.01840.2767-0.0339-0.2164-0.3436-0.1047-0.03870.0707-0.04230.14860.06390.06450.0237-0.04390.1748-0.0983-0.01530.19110.07920.20752.5836-5.3578-8.092
20.5850.3178-0.20124.62761.91381.14350.05590.1121-0.03570.4615-0.03780.07740.39360.1474-0.01810.0625-0.01880.00510.06430.01510.0235-1.1772-13.001-19.1599
32.55131.72031.34312.67961.18882.53830.0896-0.4150.09590.2938-0.2770.11750.6634-0.08020.18730.05440.01590.0550.1686-0.02240.06471.60428.97655.8909
4-0.73770.19170.16051.09950.2983-0.3357-0.0215-0.0666-0.1505-0.53510.38740.1973-0.41280.1589-0.36580.18860.0002-0.00010.1885-0.00010.18850.7445-2.8304-10.3181
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1BF134 - 15155 - 66
2X-RAY DIFFRACTION2AA449 - 5966 - 153
3X-RAY DIFFRACTION2AA614 - 722171 - 279
4X-RAY DIFFRACTION2AC21
5X-RAY DIFFRACTION2AE724 - 7871 - 64
6X-RAY DIFFRACTION3BB449 - 5956 - 152
7X-RAY DIFFRACTION3BB614 - 722171 - 279
8X-RAY DIFFRACTION3BD31
9X-RAY DIFFRACTION3AE788 - 81065 - 87
10X-RAY DIFFRACTION4BF118 - 12549 - 54

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