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- PDB-7p3v: B-Raf V600E structure bound to a new inhibitor -

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Basic information

Entry
Database: PDB / ID: 7p3v
TitleB-Raf V600E structure bound to a new inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsONCOPROTEIN / Inhibitor complex / drug design / domain swapping
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 / 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-5I4 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsSchneider, M. / Gelin, M. / Cohen-Gonsaud, M. / Labesse, G.
Funding support France, 1items
OrganizationGrant numberCountry
French Infrastructure for Integrated Structural Biology (FRISBI)ANR-10-INBS-0005 France
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Based and Knowledge-Informed Design of B-Raf Inhibitors Devoid of Deleterious PXR Binding.
Authors: Schneider, M. / Delfosse, V. / Gelin, M. / Grimaldi, M. / Granell, M. / Heriaud, L. / Pons, J.L. / Cohen Gonsaud, M. / Balaguer, P. / Bourguet, W. / Labesse, G.
History
DepositionJul 8, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 3, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Refinement description / Category: citation / citation_author / refine
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _refine.pdbx_diffrn_id
Revision 1.2Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)63,9374
Polymers62,8402
Non-polymers1,0972
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4410 Å2
ΔGint-27 kcal/mol
Surface area24260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.632, 104.854, 109.557
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS oper: (Code: givenMatrix: (-0.863872099944, 0.46717574638, -0.188339631867), (0.473120514101, 0.880871707571, 0.014900132163), (0.17286403349, -0.0762355349932, -0.981990921104)Vector: 22. ...NCS oper: (Code: given
Matrix: (-0.863872099944, 0.46717574638, -0.188339631867), (0.473120514101, 0.880871707571, 0.014900132163), (0.17286403349, -0.0762355349932, -0.981990921104)
Vector: 22.9103544064, -8.00946897301, -73.1206916541)

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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: 31420.039 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-5I4 / ~{N}-[3-[5-(2-azanylpyrimidin-4-yl)-2-[(3~{S})-morpholin-3-yl]-1,3-thiazol-4-yl]-2-fluoranyl-phenyl]-2,5-bis(fluoranyl)benzenesulfonamide


Mass: 548.561 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H19F3N6O3S2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.5 Å3/Da / Density % sol: 50.83 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 100 mM BisTrisPropane, 20% PEG 3350, and 250 mM Na-formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 28, 2019
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.37→48.55 Å / Num. obs: 47486 / % possible obs: 99.7 % / Redundancy: 6.5 % / Biso Wilson estimate: 55.77 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.128 / Rpim(I) all: 0.054 / Rrim(I) all: 0.139 / Net I/av σ(I): 9.84 / Net I/σ(I): 9.84
Reflection shellResolution: 2.37→2.46 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 0.72 / Num. unique obs: 4643 / CC1/2: 0.37 / CC star: 0.735 / Rpim(I) all: 0.9099 / % possible all: 97.9

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
PHENIX1.19.1_4122refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XV2

4xv2


Resolution: 2.37→48.55 Å / SU ML: 0.404 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.4461
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2469 3774 7.96 %Random selection
Rwork0.195 43664 --
obs0.1991 47438 99.74 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.57 Å2
Refinement stepCycle: LAST / Resolution: 2.37→48.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4191 0 74 125 4390
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00854363
X-RAY DIFFRACTIONf_angle_d1.05695900
X-RAY DIFFRACTIONf_chiral_restr0.0554633
X-RAY DIFFRACTIONf_plane_restr0.0077752
X-RAY DIFFRACTIONf_dihedral_angle_d8.1064586
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.37-2.40.44251530.40761564X-RAY DIFFRACTION95.55
2.4-2.430.43221370.38171573X-RAY DIFFRACTION98.84
2.43-2.460.39051330.37111606X-RAY DIFFRACTION100
2.46-2.50.32391330.34791674X-RAY DIFFRACTION100
2.5-2.540.32561530.29241579X-RAY DIFFRACTION99.88
2.54-2.580.27661210.28511606X-RAY DIFFRACTION99.94
2.58-2.620.36271470.27681655X-RAY DIFFRACTION99.94
2.62-2.660.33871550.2791596X-RAY DIFFRACTION100
2.66-2.710.31381190.26991639X-RAY DIFFRACTION100
2.71-2.770.32741350.25351657X-RAY DIFFRACTION99.83
2.77-2.820.29151420.24911601X-RAY DIFFRACTION100
2.82-2.880.32741340.2421617X-RAY DIFFRACTION99.94
2.88-2.950.27191500.24981601X-RAY DIFFRACTION100
2.95-3.020.30111280.24891640X-RAY DIFFRACTION100
3.02-3.110.28431500.22371616X-RAY DIFFRACTION100
3.11-3.20.29881280.19971615X-RAY DIFFRACTION99.94
3.2-3.30.23981530.18931632X-RAY DIFFRACTION100
3.3-3.420.22241460.17761605X-RAY DIFFRACTION99.94
3.42-3.550.24291310.17291648X-RAY DIFFRACTION99.89
3.55-3.720.2311430.16861612X-RAY DIFFRACTION100
3.72-3.910.25221370.16341642X-RAY DIFFRACTION99.78
3.91-4.160.21771390.15681580X-RAY DIFFRACTION100
4.16-4.480.17731480.13481632X-RAY DIFFRACTION100
4.48-4.930.22431470.15131596X-RAY DIFFRACTION99.94
4.93-5.640.1961240.16661647X-RAY DIFFRACTION99.94
5.64-7.10.24051440.20091616X-RAY DIFFRACTION99.94
7.1-48.550.21671440.18221615X-RAY DIFFRACTION99.77
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)
16.102139427421.620886059330.9082767865244.67552493784-0.5222305361495.43503670618-0.03433030930910.8041245449870.074784128337-0.406009663522-0.04336285795380.480338916589-0.0066742005798-0.6932142232720.09784865727920.4838668069320.0562575826577-0.02162530139520.576879800108-0.01903695036940.39964580396219.51069491325.23326953889-22.4685296156
22.25180233267-0.5148293045871.173025894624.487496436470.5461144772884.43058778578-0.01393733336540.100645310036-0.1479532999770.4602821670460.217815899061-0.3554003588010.3289500994410.283669295419-0.2045980888440.471185206186-0.0406919725283-0.0527041541750.470932426579-0.06591483645380.42423291907527.6754886899-8.84271431045-15.3970639418
32.776495562071.053611095724.82280248681-0.02621488563080.6406570710035.521785591430.299568468399-0.0207141024122-0.16477497904-0.007952323602940.0779885855441-0.1775228118030.118668292574-0.328503957094-0.3437593133990.604547666019-0.0343285492923-0.07302510047050.7115375036780.03550647622140.56476145199810.0367245265-15.526825796-29.5287921323
43.239733462160.459666004738-0.1284077540724.025932790942.731536666396.77779338610.217245363383-0.224825775429-0.4443330732771.16943005390.193649478946-0.3106398702921.238819473970.396371388281-0.2707346606940.8203290412530.0300288639707-0.1299046440920.4476718018340.01249138773660.64643011978227.9716391924-27.1093592483-19.4080337681
51.95742853034-0.7273939566670.9753738521824.357717286340.6791865695465.28160086971-0.181161963169-0.3286938862610.1358445688630.524711818440.147363273458-0.318635887545-0.5919071732290.6497590731550.2045848301780.738444924322-0.114330564552-0.08874949912760.849532683024-0.0478243040950.52251286362512.67056551245.36406689142-48.0932873978
63.013394137971.32344548099-1.191448894063.98779972633-0.7917189641142.833783128230.102155068236-0.3610312924050.2332730797530.296775664405-0.1271306388610.253577900266-0.821749301673-0.04935073103380.02456861238560.5084894442570.0526857743313-0.0374636515620.535260220596-0.0130463901870.385353880729-2.37210160629-2.96500837934-52.803313869
78.05238223079-3.518167159529.386641630340.839989428212-3.43965710657.537107050550.2263431051111.335494818040.936389737401-0.254536488376-0.491403652763-0.002270758434160.1987814941390.8180839416170.1751923138620.7096626432410.03652053229110.001361571126230.8966097834210.08834425222260.76954452942317.1677351581-15.6023301891-37.9419937063
85.234987997530.109147287567-1.043360717445.92059829137-2.638687622577.892736850660.0678691217682-0.25435984791-0.431507004161-0.1040616920590.1246072904030.2408145172140.120400009616-0.50020295893-0.03505332003330.345981309074-0.0183968989111-0.003574900931670.545917960046-0.01358834522910.49413415556-10.0821527577-19.2844748674-47.5243959585
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 447 through 507 )AA447 - 5071 - 61
22chain 'A' and (resid 508 through 587 )AA508 - 58762 - 141
33chain 'A' and (resid 588 through 634 )AA588 - 634142 - 171
44chain 'A' and (resid 635 through 721 )AA635 - 721172 - 258
55chain 'B' and (resid 448 through 507 )BB448 - 5071 - 60
66chain 'B' and (resid 508 through 592 )BB508 - 59261 - 145
77chain 'B' and (resid 593 through 634 )BB593 - 634146 - 187
88chain 'B' and (resid 635 through 719 )BB635 - 719188 - 272

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