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- PDB-6xgu: Crystal Structure of KRAS-Q61R (GMPPNP-bound) in complex with RAS... -

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Basic information

Entry
Database: PDB / ID: 6xgu
TitleCrystal Structure of KRAS-Q61R (GMPPNP-bound) in complex with RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF1/CRAF
Components
  • GTPase KRas
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsONCOPROTEIN/Transferase / KRAS / RAS / K-ras / KRAS4b / Q61R / 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 / 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 / neurotrophin TRK receptor signaling pathway / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / face development / pseudopodium / Rac protein signal transduction / regulation of cell differentiation / thyroid gland development / positive regulation of Rac protein signal transduction / 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 / extrinsic apoptotic signaling pathway via death domain receptors / SOS-mediated signalling / somatic stem cell population maintenance / Activated NTRK3 signals through RAS / 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 / Schwann cell development / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / negative regulation of protein-containing complex assembly / 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 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / response to muscle stretch / striated muscle cell differentiation / Signaling by FGFR2 in disease / myelination / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / insulin-like growth factor receptor signaling pathway / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / 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: 2.7 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.journal_volume / _citation.page_first ..._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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)36,1739
Polymers35,2462
Non-polymers9277
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3900 Å2
ΔGint-16 kcal/mol
Surface area14930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)132.320, 132.320, 89.910
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number177
Space group name H-MP622

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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: 19357.875 Da / Num. of mol.: 1 / Mutation: Q61R
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: 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 , 5 types, 31 molecules

#3: 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
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.21 Å3/Da / Density % sol: 61.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 100 mM Tris 7.8, 200 mM KBr, 200 mM KSCN, 3% PGA, 0.35 mM D-myo-phosphatidylinositol 3,4,5-triphosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.7→48.32 Å / Num. obs: 13291 / % possible obs: 99.8 % / Redundancy: 12.125 % / Biso Wilson estimate: 82.772 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.069 / Rrim(I) all: 0.073 / Χ2: 0.84 / Net I/σ(I): 25.35
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
2.78-2.9512.1050.8342.9623144192119120.9270.8799.5
2.95-3.1512.8830.4546.1623305181118090.9790.47299.9
3.15-3.412.2760.24511.5920759169216910.9910.25699.9
3.4-3.7212.3060.12621.1219370157415740.9970.131100
3.72-4.1612.5330.07633.8117859142514250.9990.08100
4.16-4.7911.6820.05245.2414918127812770.9990.05499.9
4.79-5.8612.2420.05148.2113417109610960.9990.053100
5.86-8.2211.0330.04552.5297978908880.9990.04799.8
8.22-48.3210.2230.03463.455925565470.9980.03698.4

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6XHB

6xhb


Resolution: 2.7→48.32 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2357 1329 10 %
Rwork0.1873 11960 -
obs0.1922 13289 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 201.19 Å2 / Biso mean: 94.6213 Å2 / Biso min: 46.94 Å2
Refinement stepCycle: final / Resolution: 2.7→48.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2406 0 48 24 2478
Biso mean--95.32 75.27 -
Num. residues----302
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7-2.80.43961410.37051274141598
2.8-2.930.30661440.260612891433100
2.93-3.090.28711440.219413021446100
3.09-3.280.28621460.223913141460100
3.28-3.530.26271450.189412991444100
3.53-3.890.23781480.178613371485100
3.89-4.450.21421470.158813261473100
4.45-5.60.19361520.166113621514100
5.61-48.320.2281620.185814571619100
Refinement TLS params.Method: refined / Origin x: 36.8091 Å / Origin y: 40.8289 Å / Origin z: 20.0497 Å
111213212223313233
T0.7432 Å20.1847 Å2-0.0649 Å2-0.4856 Å20.0558 Å2--0.5348 Å2
L3.176 °2-0.4306 °2-0.026 °2-3.8244 °21.5892 °2--3.4604 °2
S0.1584 Å °0.4062 Å °-0.1025 Å °-0.7831 Å °-0.1011 Å °0.1062 Å °0.2277 Å °0.0763 Å °-0.1043 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 168
2X-RAY DIFFRACTION1allB55 - 188
3X-RAY DIFFRACTION1allW1 - 24
4X-RAY DIFFRACTION1allL1 - 8

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