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- PDB-6vjj: Crystal Structure of wild-type KRAS4b (GMPPNP-bound) in complex w... -

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Basic information

Entry
Database: PDB / ID: 6vjj
TitleCrystal Structure of wild-type KRAS4b (GMPPNP-bound) in complex with RAS-binding domain (RBD) of RAF1/CRAF
Components
  • GTPase KRas
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsONCOPROTEIN / KRAS / RAS / K-ras / KRAS4b / RAF1 / CRAF / RBD / RAS-binding domain
Function / homology
Function and homology information


death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / regulation of Rho protein signal transduction / type B pancreatic cell proliferation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / insulin secretion involved in cellular response to glucose stimulus / response to mineralocorticoid / GMP binding ...death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / regulation of Rho protein signal transduction / type B pancreatic cell proliferation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / insulin secretion involved in cellular response to glucose stimulus / response to mineralocorticoid / GMP binding / Negative feedback regulation of MAPK pathway / forebrain astrocyte development / IFNG signaling activates MAPKs / LRR domain binding / GP1b-IX-V activation signalling / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / ERBB2-ERBB3 signaling pathway / response to gravity / epithelial tube branching involved in lung morphogenesis / neurotrophin TRK receptor signaling pathway / type I pneumocyte differentiation / pseudopodium / Rac protein signal transduction / face development / positive regulation of Rac protein signal transduction / regulation of cell differentiation / thyroid gland development / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / extrinsic apoptotic signaling pathway via death domain receptors / Activated NTRK3 signals through RAS / somatic stem cell population maintenance / Activated NTRK2 signals through RAS / positive regulation of peptidyl-serine phosphorylation / SHC1 events in ERBB4 signaling / MAP kinase kinase kinase activity / cardiac muscle cell proliferation / Signalling to RAS / type II interferon-mediated signaling pathway / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / negative regulation of protein-containing complex assembly / Schwann cell development / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / response to muscle stretch / Signaling by FGFR2 in disease / myelination / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / insulin-like growth factor receptor signaling pathway / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / thymus development / adenylate cyclase activator activity / VEGFR2 mediated cell proliferation
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) ...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 / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Ubiquitin-like domain superfamily / P-loop containing nucleotide triphosphate hydrolases / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas / RAF proto-oncogene serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsTran, T.H. / Dharmaiah, S. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: Nat Commun / Year: 2021
Title: KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation.
Authors: Tran, T.H. / Chan, A.H. / Young, L.C. / Bindu, L. / Neale, C. / Messing, S. / Dharmaiah, S. / Taylor, T. / Denson, J.P. / Esposito, D. / Nissley, D.V. / Stephen, A.G. / McCormick, F. / Simanshu, D.K.
History
DepositionJan 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 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: GTPase KRas
B: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,33110
Polymers28,4352
Non-polymers8958
Water2,612145
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Heterodimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.132, 67.572, 71.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19328.811 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116
#2: Protein RAF proto-oncogene serine/threonine-protein kinase / Proto-oncogene c-RAF / cRaf / Raf-1


Mass: 9106.649 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAF1, RAF / Production host: Escherichia coli (E. coli)
References: UniProt: P04049, non-specific serine/threonine protein kinase

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Non-polymers , 6 types, 153 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 1.88 Å3/Da / Density % sol: 34.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.09M Halogens, 0.1M Imidazole.MES pH 6.5, 37.5% MPD, PEG 1000 and PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.4→49.03 Å / Num. obs: 81103 / % possible obs: 99.9 % / Redundancy: 4.782 % / Biso Wilson estimate: 22.513 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.064 / Rrim(I) all: 0.072 / Χ2: 1.076 / Net I/σ(I): 12.58 / Num. measured all: 387827 / Scaling rejects: 13
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.4-1.444.4020.6872.1826517602360240.7720.782100
1.44-1.484.8110.5752.8128036582858270.8420.647100
1.48-1.524.7970.4763.3127433572057190.8840.537100
1.52-1.574.6560.3554.3925432546454620.9220.401100
1.57-1.624.6610.2945.1125099538553850.9480.332100
1.62-1.674.9710.2316.5225787518851870.970.259100
1.67-1.744.9180.2067.1824606500450030.9720.231100
1.74-1.814.8550.1519.3323236478647860.9840.169100
1.81-1.894.5020.11711.2320876464446370.9880.13399.8
1.89-1.984.9580.09714.4621743438643850.9920.108100
1.98-2.095.0050.07817.4421010420041980.9940.087100
2.09-2.214.9250.0719.4419635399139870.9960.07899.9
2.21-2.374.6110.06120.817030370136930.9960.06999.8
2.37-2.564.8350.05623.5616744346734630.9960.06299.9
2.56-2.85.0140.05425.2616071320732050.9970.0699.9
2.8-3.134.870.04927.4713973286928690.9970.055100
3.13-3.614.4470.04528.1611269254925340.9970.0599.4
3.61-4.435.0190.04132.0510850216221620.9980.046100
4.43-6.264.8450.03831.528067166616650.9980.04299.9
6.26-49.034.8390.03731.444139149120.9980.04199.8

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Processing

Software
NameVersionClassification
PHENIX1.17_3644refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4G0N

4g0n


Resolution: 1.4→49.03 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.23
RfactorNum. reflection% reflection
Rfree0.1949 2001 4.69 %
Rwork0.1645 --
obs0.1659 42703 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 59.51 Å2 / Biso mean: 21.1196 Å2 / Biso min: 9.31 Å2
Refinement stepCycle: final / Resolution: 1.4→49.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1917 0 52 145 2114
Biso mean--22.31 29.96 -
Num. residues----245
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.4-1.440.2331420.222828793021
1.44-1.470.22331470.211628533000
1.47-1.520.24471380.199928612999
1.52-1.570.20611360.181828562992
1.57-1.620.1891440.173528753019
1.62-1.690.1621430.168728823025
1.69-1.760.19291380.168728813019
1.76-1.860.21031440.166928873031
1.86-1.970.1661390.155528933032
1.97-2.130.19861380.156129173055
2.13-2.340.161450.159429163061
2.34-2.680.18881470.162429093056
2.68-3.370.18641440.161929943138
3.37-49.030.21511560.157530993255
Refinement TLS params.Method: refined / Origin x: -13.9654 Å / Origin y: -12.769 Å / Origin z: 20.5787 Å
111213212223313233
T0.1075 Å2-0.0014 Å20.0078 Å2-0.1087 Å2-0.0106 Å2--0.122 Å2
L0.5865 °2-0.0799 °20.3111 °2-0.521 °2-0.3074 °2--1.21 °2
S-0.0124 Å °-0.0131 Å °0.0152 Å °0.0319 Å °0.0116 Å °0.0132 Å °0.0039 Å °-0.0059 Å °-0.0001 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA0 - 167
2X-RAY DIFFRACTION1allB55 - 131
3X-RAY DIFFRACTION1allS1 - 145
4X-RAY DIFFRACTION1allL1 - 8

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