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- PDB-6xhb: Crystal Structure of wild-type KRAS (GMPPNP-bound) in complex wit... -

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Entry
Database: PDB / ID: 6xhb
TitleCrystal Structure of wild-type KRAS (GMPPNP-bound) in complex with RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF1/CRAF (crystal form II)
Components
  • GTPase KRas
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsONCOPROTEIN/Transferase / KRAS / RAS / K-ras / KRAS4b / RAF1 / CRAF / RBD / RAS-binding domain / cysteine-rich domain / CRD / ONCOPROTEIN / ONCOPROTEIN-Transferase complex
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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / somatic stem cell population maintenance / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / neurotrophin TRK receptor signaling pathway / thyroid gland development / 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 / MAP kinase kinase kinase activity / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / SHC-related events triggered by IGF1R / 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 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Schwann cell development / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / type II interferon-mediated signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / protein-membrane adaptor activity / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 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 / EGFR Transactivation by Gastrin / response to muscle stretch / myelination / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / Signaling by FGFR1 in disease / 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 / small monomeric GTPase / insulin-like growth factor receptor signaling pathway / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / thymus development / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII
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 / ISOPROPYL ALCOHOL / GTPase KRas / RAF proto-oncogene serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsTran, T.H. / Chan, A.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
DepositionJun 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2021Provider: 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 18, 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)36,24512
Polymers35,2172
Non-polymers1,02810
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4440 Å2
ΔGint-40 kcal/mol
Surface area14890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)133.984, 133.984, 89.275
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number177
Space group name H-MP622
Components on special symmetry positions
IDModelComponents
11B-350-

HOH

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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: 15888.440 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 , 7 types, 97 molecules

#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / 5'-Guanylyl imidodiphosphate


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
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 3.27 Å3/Da / Density % sol: 62.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 100 mM sodium cacodylate pH 6.5, 200 mM sodium citrate, 15% 2-propanol, 0.25% (w/v) n-octyl-beta-D-glucoside, 0.35 mM D-myo-phosphatidylinositol 3,4,5-triphosphate, and 0.25% (w/v) n-dodecyl-beta-D-maltoside

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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 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.5→48.65 Å / Num. obs: 16642 / % possible obs: 98.4 % / Redundancy: 6.164 % / Biso Wilson estimate: 59.192 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.089 / Rrim(I) all: 0.097 / Χ2: 1.151 / Net I/σ(I): 14.03 / Num. measured all: 102583
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
2.5-2.656.2650.861.9116570266626450.740.93799.2
2.65-2.836.1430.5572.9615284250724880.8670.60899.2
2.83-3.066.1150.3145.1414273235223340.9560.34299.2
3.06-3.356.4690.1789.3113831216621380.9850.19498.7
3.35-3.746.2790.10415.512282198519560.9950.11498.5
3.74-4.325.8240.06323.8910040175817240.9970.0798.1
4.32-5.286.3580.04931.869372151214740.9990.05397.5
5.28-7.426.0430.04931.797107121311760.9980.05396.9
7.42-48.655.4090.02847.0838247577070.9990.03193.4

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.17.1_3660refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VJJ, 1FAR

6vjj

1far


Resolution: 2.5→48.65 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2213 1664 10 %
Rwork0.1863 14974 -
obs0.19 16638 98.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 153.86 Å2 / Biso mean: 62.1845 Å2 / Biso min: 29.91 Å2
Refinement stepCycle: final / Resolution: 2.5→48.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2402 0 54 87 2543
Biso mean--64.62 57.46 -
Num. residues----300
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5-2.570.37091370.29571228136599
2.57-2.660.29271350.26321225136099
2.66-2.750.2981370.2531222135999
2.75-2.860.33441380.23891251138999
2.86-2.990.2791360.22631219135599
2.99-3.150.28531390.21341247138699
3.15-3.350.2471350.20261230136599
3.35-3.60.20561380.1861242138099
3.6-3.970.24871390.16151252139199
3.97-4.540.16621380.14811243138198
4.54-5.720.18341420.15951277141997
5.72-48.650.1891500.18011338148895
Refinement TLS params.Method: refined / Origin x: 37.193 Å / Origin y: 41.5923 Å / Origin z: 20.3208 Å
111213212223313233
T0.4004 Å20.0754 Å2-0.0168 Å2-0.356 Å2-0.0003 Å2--0.3743 Å2
L1.2789 °2-0.2875 °2-0.1255 °2-1.7798 °20.6735 °2--1.7532 °2
S0.1036 Å °0.2048 Å °-0.1171 Å °-0.1913 Å °-0.0669 Å °-0.0053 Å °0.1926 Å °0.0304 Å °-0.048 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 168
2X-RAY DIFFRACTION1allB55 - 188
3X-RAY DIFFRACTION1allW1 - 87
4X-RAY DIFFRACTION1allL1 - 10

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