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- PDB-8t74: Crystal structure of KRAS4a (GMPPNP) in complex with RAF1 (RBD) -

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Basic information

Entry
Database: PDB / ID: 8t74
TitleCrystal structure of KRAS4a (GMPPNP) in complex with RAF1 (RBD)
Components
  • GTPase KRas
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsONCOPROTEIN / RAS / KRAS / RAF1 / CRAF
Function / homology
Function and homology information


death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / forebrain astrocyte development ...death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / forebrain astrocyte development / Negative feedback regulation of MAPK pathway / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / IFNG signaling activates MAPKs / GP1b-IX-V activation signalling / ERBB2-ERBB3 signaling pathway / Rac protein signal transduction / regulation of cell differentiation / face development / skeletal muscle cell differentiation / pseudopodium / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / somatic stem cell population maintenance / thyroid gland development / neurotrophin TRK receptor signaling pathway / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / extrinsic apoptotic signaling pathway via death domain receptors / SHC1 events in ERBB4 signaling / MAP kinase kinase kinase activity / Signalling to RAS / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / negative regulation of protein-containing complex assembly / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / type II interferon-mediated signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / activation of adenylate cyclase activity / response to muscle stretch / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / insulin-like growth factor receptor signaling pathway / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / thymus development / G protein activity / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / wound healing
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 / Small GTPase, Ras-type / small GTPase Ras family 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 / 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 / P-loop containing nucleoside triphosphate hydrolase
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: 1.65 Å
AuthorsWhitley, M.J. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: Sci Adv / Year: 2024
Title: Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties.
Authors: Whitley, M.J. / Tran, T.H. / Rigby, M. / Yi, M. / Dharmaiah, S. / Waybright, T.J. / Ramakrishnan, N. / Perkins, S. / Taylor, T. / Messing, S. / Esposito, D. / Nissley, D.V. / McCormick, F. / ...Authors: Whitley, M.J. / Tran, T.H. / Rigby, M. / Yi, M. / Dharmaiah, S. / Waybright, T.J. / Ramakrishnan, N. / Perkins, S. / Taylor, T. / Messing, S. / Esposito, D. / Nissley, D.V. / McCormick, F. / Stephen, A.G. / Turbyville, T. / Cornilescu, G. / Simanshu, D.K.
History
DepositionJun 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)30,0794
Polymers29,5332
Non-polymers5472
Water3,549197
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.371, 37.703, 70.876
Angle α, β, γ (deg.)90.000, 101.670, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 20426.123 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, small monomeric GTPase
#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
#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
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.48 Å3/Da / Density % sol: 50.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.15 M DL-malic acid (pH 7.0), 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 23, 2022
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.65→46.52 Å / Num. obs: 31826 / % possible obs: 94.6 % / Redundancy: 3.3 % / Biso Wilson estimate: 25.2 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.043 / Rrim(I) all: 0.051 / Net I/σ(I): 15.4
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.65-1.750.56441280.7090.7251
1.75-1.870.39149660.8840.4691
1.87-2.020.21446560.9670.2531
2.02-2.210.12242920.9860.1461
2.21-2.470.07438570.9940.0881
2.47-2.850.05134560.9960.061
2.85-3.490.03228830.9980.0381
3.49-4.930.02522790.9990.031
4.93-46.520.0213100.9990.0241

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
PHASERphasing
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.28data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→46.52 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 23.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1958 1511 4.75 %
Rwork0.1728 30302 -
obs0.1739 31813 94.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 148.55 Å2 / Biso mean: 42.6345 Å2 / Biso min: 15.82 Å2
Refinement stepCycle: final / Resolution: 1.65→46.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1907 0 46 197 2150
Biso mean--26.49 40.32 -
Num. residues----238
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032007
X-RAY DIFFRACTIONf_angle_d0.7092717
X-RAY DIFFRACTIONf_chiral_restr0.052307
X-RAY DIFFRACTIONf_plane_restr0.006346
X-RAY DIFFRACTIONf_dihedral_angle_d13.238768
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.65-1.70.43341020.39062044214671
1.7-1.760.33491240.31042490261486
1.76-1.840.24451400.23762819295998
1.84-1.920.2541440.19632894303899
1.92-2.020.20181410.18282823296499
2.02-2.150.22121420.18272844298698
2.15-2.310.17391410.15672833297498
2.31-2.540.21421440.15792875301999
2.54-2.910.20051420.17242860300298
2.91-3.670.19691430.15762862300597
3.67-46.520.15981480.15882958310698
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)
12.7795-0.74960.76733.7081-0.98932.6472-0.0141-0.1082-0.15110.09120.09550.2890.1627-0.1964-0.08840.1819-0.00350.03370.1882-0.0030.18799.93892.801310.9413
28.2291-5.15021.15255.7022-0.56735.7483-0.2233-0.72450.30590.15230.04920.5506-0.1459-0.9822-0.29470.12-0.0232-0.04470.4609-0.01870.4334-3.44124.91915.4651
31.5195-0.66-0.74775.081-0.04221.26380.0251-0.07810.04650.37090.04350.2811-0.1260.0028-0.08350.2286-0.00580.01690.2332-0.01630.203511.96657.250915.1041
44.62231.85542.63773.04571.33785.4944-0.1340.13320.31020.07660.08530.0771-0.33920.22680.05210.2086-0.00690.01040.19260.00340.222718.609816.21454.575
54.10820.392-0.73632.6141-0.30411.1646-0.07780.3213-0.122-0.21930.0558-0.1035-0.11560.0530.0360.20640.0003-0.00790.2306-0.00660.19917.09998.3817-3.0088
64.7837-2.07121.3472.8371-0.93932.14460.0941-0.0259-0.0346-0.0383-0.014-0.02050.15980.0778-0.09980.1581-0.0065-0.00320.16790.00070.14518.1806-1.66656.1258
77.5696-1.69630.83137.3902-3.48381.65910.2179-0.11661.36830.58090.1584-0.678-1.114-0.2595-0.20610.79460.13520.16330.4047-0.06110.55950.98416.368925.0845
84.1989-0.5568-0.79839.630.6014.3671-0.0399-0.5432-0.00870.73370.2239-0.34260.09930.0847-0.16510.40180.02310.06030.3457-0.00720.25065.41444.267424.4237
92.69861.89172.00569.090.1332.6391-0.58370.62650.78810.28330.44561.4191-0.4547-1.02790.07480.68890.270.17540.58590.13730.5968-4.773416.606221.3892
103.7324-2.7756-3.75547.74923.50394.0332-0.03510.3035-0.22260.3376-0.15961.27380.0706-1.23430.03020.4109-0.00330.09970.5818-0.02220.5151-5.86814.915920.2055
116.58250.50032.02187.69654.38353.4287-0.7683-0.5531-0.89150.1220.04240.57420.9915-1.12190.70690.9104-0.05110.34710.76810.07330.5729-5.40322.030129.8359
122.54050.19141.50644.88530.22354.82170.1563-0.8518-0.18250.8428-0.15721.0754-0.264-0.77240.32220.89890.14690.33720.8857-0.05520.6372-7.81019.54532.3884
138.44770.49260.1523.573-3.62273.7239-0.5438-0.89530.33380.7399-0.4628-0.46920.3463-0.16390.95430.82960.05440.00670.56280.0070.3624-0.49986.614830.8087
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 1:26)A1 - 26
2X-RAY DIFFRACTION2(chain A and resid 27:31)A27 - 31
3X-RAY DIFFRACTION3(chain A and resid 32:79)A32 - 79
4X-RAY DIFFRACTION4(chain A and resid 80:106)A80 - 106
5X-RAY DIFFRACTION5(chain A and resid 107:145)A107 - 145
6X-RAY DIFFRACTION6(chain A and resid 146:170)A146 - 170
7X-RAY DIFFRACTION7(chain B and resid 56:59)B56 - 59
8X-RAY DIFFRACTION8(chain B and resid 60:69)B60 - 69
9X-RAY DIFFRACTION9(chain B and resid 70:75)B70 - 75
10X-RAY DIFFRACTION10(chain B and resid 76:91)B76 - 91
11X-RAY DIFFRACTION11(chain B and resid 92:101)B92 - 101
12X-RAY DIFFRACTION12(chain B and resid 102:121)B102 - 121
13X-RAY DIFFRACTION13(chain B and resid 122:131)B122 - 131

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