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- PDB-3idp: B-Raf V600E kinase domain in complex with an aminoisoquinoline in... -

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Basic information

Entry
Database: PDB / ID: 3idp
TitleB-Raf V600E kinase domain in complex with an aminoisoquinoline inhibitor
ComponentsB-Raf proto-oncogene serine/threonine-protein kinase
KeywordsTRANSFERASE / oncogene / ATP-binding / DFG-out / Cardiomyopathy / Disease mutation / Kinase / Metal-binding / Nucleotide-binding / Phorbol-ester binding / Phosphoprotein / Proto-oncogene / Serine/threonine-protein kinase / Zinc-finger
Function / homology
Function and homology information


trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / 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 ...trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / 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 / ERK1 and ERK2 cascade / cellular response to calcium ion / 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 / cell body / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / regulation of cell population proliferation / T cell receptor signaling pathway / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / neuron projection / protein kinase activity / protein phosphorylation / protein serine kinase activity / intracellular membrane-bounded organelle / 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-L1E / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsWhittington, D.A. / Epstein, L.F.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Selective inhibitors of the mutant B-raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.
Authors: Smith, A.L. / Demorin, F.F. / Paras, N.A. / Huang, Q. / Petkus, J.K. / Doherty, E.M. / Nixey, T. / Kim, J.L. / Whittington, D.A. / Epstein, L.F. / Lee, M.R. / Rose, M.J. / Babij, C. / ...Authors: Smith, A.L. / Demorin, F.F. / Paras, N.A. / Huang, Q. / Petkus, J.K. / Doherty, E.M. / Nixey, T. / Kim, J.L. / Whittington, D.A. / Epstein, L.F. / Lee, M.R. / Rose, M.J. / Babij, C. / Fernando, M. / Hess, K. / Le, Q. / Beltran, P. / Carnahan, J.
History
DepositionJul 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Oct 13, 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
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)69,9864
Polymers69,0282
Non-polymers9582
Water1,42379
1
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9932
Polymers34,5141
Non-polymers4791
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9932
Polymers34,5141
Non-polymers4791
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.457, 93.457, 166.679
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: TRP / Beg label comp-ID: TRP / End auth comp-ID: ARG / End label comp-ID: ARG / Auth seq-ID: 450 - 719 / Label seq-ID: 23 - 292

Dom-IDAuth asym-IDLabel asym-ID
1AB
2BA

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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: 34513.848 Da / Num. of mol.: 2 / Fragment: kinase domain / Mutation: V600E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-L1E / N~1~-(4-chlorophenyl)-6-methyl-N~5~-[3-(7H-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine / N5-(3-(9H-purin-6-yl)pyridin-2-yl)-N1-(4-chlorophenyl)-6-methylisoquinoline-1,5-diamine


Mass: 478.936 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H19ClN8
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.64 Å3/Da / Density % sol: 53.34 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8.6
Details: 17% PEG 8000, 75 mM sodium succinate, 0.1 M Tris, pH 8.6, VAPOR DIFFUSION, temperature 298K

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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 315 / Detector: CCD / Date: Jul 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. all: 21050 / Num. obs: 19744 / % possible obs: 93.8 % / Redundancy: 5.9 % / Biso Wilson estimate: 61.5 Å2 / Rmerge(I) obs: 0.133 / Χ2: 1.553 / Net I/σ(I): 15.3
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 2 / Num. unique all: 1399 / Χ2: 0.742 / % possible all: 68.7

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT1.401data extraction
DENZOdata reduction
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1UWH

1uwh


Resolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.901 / SU B: 21.292 / SU ML: 0.221 / SU R Cruickshank DPI: 1.061 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R Free: 0.36
RfactorNum. reflection% reflectionSelection details
Rfree0.264 1556 7.9 %RANDOM
Rwork0.201 ---
all0.206 ---
obs-19724 94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.574 Å2
Baniso -1Baniso -2Baniso -3
1-0.47 Å20 Å20 Å2
2--0.47 Å20 Å2
3----0.95 Å2
Refinement stepCycle: LAST / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4085 0 70 79 4234
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONr_bond_refined_d0.00842540.022
X-RAY DIFFRACTIONr_angle_refined_deg1.1357461.981
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4155065
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.59318323.77
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.1776915
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.52615
X-RAY DIFFRACTIONr_chiral_restr0.0796240.2
X-RAY DIFFRACTIONr_gen_planes_refined0.00331680.02
X-RAY DIFFRACTIONr_nbd_refined0.19917980.2
X-RAY DIFFRACTIONr_nbtor_refined0.30928960.2
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1391520.2
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.219420.2
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.14230.2
X-RAY DIFFRACTIONr_mcbond_it0.79826002
X-RAY DIFFRACTIONr_mcangle_it1.41641053
X-RAY DIFFRACTIONr_scbond_it1.17919263
X-RAY DIFFRACTIONr_scangle_it1.86616414.5
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
1004MEDIUM POSITIONAL0.270.5
1007LOOSE POSITIONAL0.555
1004MEDIUM THERMAL0.42
1007LOOSE THERMAL1.2910
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 89 -
Rwork0.287 916 -
obs--66.82 %
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)
11.73660.01790.05671.50530.11523.1463-0.00570.085-0.0398-0.1362-0.03870.1926-0.0138-0.09650.0444-0.0202-0.0094-0.0028-0.05060.0021-0.07532.066329.519427.2281
21.06060.4578-0.28681.5754-0.29570.71580.0369-0.0844-0.02120.0683-0.00920.0209-0.0577-0.0049-0.02770.00720.01290.0056-0.03940.0097-0.08986.439516.983750.3449
31.33340.18640.23562.0413-0.40223.1783-0.1358-0.14710.25050.09240.0516-0.1036-0.2220.18610.0841-0.0087-0.0438-0.00970.0052-0.0132-0.040318.227246.407342.4853
42.13580.6434-0.75180.9728-0.63481.0802-0.0336-0.0718-0.1147-0.07220.0595-0.04840.02820.04-0.0259-0.01430.00550.0427-0.0407-0.001-0.038331.55740.719119.9376
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A449 - 533
2X-RAY DIFFRACTION2A534 - 720
3X-RAY DIFFRACTION3B449 - 533
4X-RAY DIFFRACTION4B534 - 720

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