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- PDB-8epw: Crystal Structure of KRAS4b-G13D (GMPPNP-bound) in complex with R... -

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Basic information

Entry
Database: PDB / ID: 8epw
TitleCrystal Structure of KRAS4b-G13D (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 / 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 / insulin secretion involved in cellular response to glucose stimulus / forebrain astrocyte development / Negative feedback regulation of MAPK pathway ...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 / insulin secretion involved in cellular response to glucose stimulus / forebrain astrocyte development / Negative feedback regulation of MAPK pathway / IFNG signaling activates MAPKs / negative regulation of epithelial cell differentiation / GP1b-IX-V activation signalling / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / ERBB2-ERBB3 signaling pathway / Rac protein signal transduction / face development / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / pseudopodium / regulation of cell differentiation / neurotrophin TRK receptor signaling pathway / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / thyroid gland development / RAS signaling downstream of NF1 loss-of-function variants / somatic stem cell population maintenance / RUNX3 regulates p14-ARF / extrinsic apoptotic signaling pathway via death domain receptors / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / MAP kinase kinase kinase activity / SHC1 events in ERBB4 signaling / type II interferon-mediated signaling pathway / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / negative regulation of protein-containing complex assembly / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / activation of adenylate cyclase activity / membrane-membrane adaptor activity / FRS-mediated FGFR2 signaling / positive regulation of peptidyl-serine phosphorylation / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / response to muscle stretch / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / myelination / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / Downstream signal transduction / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / insulin-like growth factor receptor signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / thymus development / small monomeric GTPase / FCERI mediated MAPK activation / RAF activation / regulation of long-term neuronal synaptic plasticity / wound healing / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT
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 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 / 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 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: Commun Biol / Year: 2023
Title: Reduced dynamic complexity allows structure elucidation of an excited state of KRAS G13D .
Authors: Chao, F.A. / Chan, A.H. / Dharmaiah, S. / Schwieters, C.D. / Tran, T.H. / Taylor, T. / Ramakrishnan, N. / Esposito, D. / Nissley, D.V. / McCormick, F. / Simanshu, D.K. / Cornilescu, G.
History
DepositionOct 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 21, 2023Group: 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 / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: 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

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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)29,0404
Polymers28,4932
Non-polymers5472
Water1,09961
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)44.480, 66.800, 71.380
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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


Mass: 19386.848 Da / Num. of mol.: 1 / Mutation: G13D
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-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 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 61 / 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: 1.86 Å3/Da / Density % sol: 33.9 % / Description: 3D plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.15 M potassium bromide, 30% PEG 2000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→48.77 Å / Num. obs: 14925 / % possible obs: 99.9 % / Redundancy: 8.699 % / Biso Wilson estimate: 32.075 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.103 / Rrim(I) all: 0.11 / Χ2: 0.883 / Net I/σ(I): 14.31 / Num. measured all: 129834 / Scaling rejects: 51
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
2-2.058.8330.6163.879513107910770.9060.65499.8
2.05-2.118.8660.5114.669442106810650.9290.54299.7
2.11-2.178.8180.465.088941101710140.9510.48899.7
2.17-2.248.7850.3526.388890101310120.970.37499.9
2.24-2.318.9230.2917.4185049539530.980.309100
2.31-2.398.880.2458.2483839469440.9850.2699.8
2.39-2.489.0580.229.4782079079060.9860.23399.9
2.48-2.589.020.18810.8378478708700.9890.199100
2.58-2.79.0040.17111.8575638408400.9910.181100
2.7-2.838.8910.14114.2971578058050.9930.15100
2.83-2.988.9180.10717.1870017857850.9950.114100
2.98-3.168.8840.09120.3964947317310.9960.097100
3.16-3.388.5490.0823.0358566856850.9960.086100
3.38-3.658.5170.06926.1554686426420.9970.073100
3.65-48.1160.06628.249186076060.9970.0799.8
4-4.477.8930.05930.143655545530.9970.06399.8
4.47-5.168.0290.05430.4638224774760.9980.05899.8
5.16-6.327.9950.05730.1933904244240.9980.061100
6.32-8.947.8260.04930.726533393390.9980.053100
8.94-48.777.1720.04731.0414202011980.9980.05198.5

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.17_3644refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VJJ

6vjj


Resolution: 2→48.77 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2528 740 4.96 %
Rwork0.1916 14175 -
obs0.1947 14915 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 114.31 Å2 / Biso mean: 38.0752 Å2 / Biso min: 14.01 Å2
Refinement stepCycle: final / Resolution: 2→48.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1895 0 33 61 1989
Biso mean--26.03 39.07 -
Num. residues----239
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2-2.150.361480.274927832931
2.15-2.370.33651440.243327752919
2.37-2.710.29121440.211428102954
2.71-3.420.27461490.188728362985
3.42-48.770.18621550.155929713126
Refinement TLS params.Method: refined / Origin x: -7.984 Å / Origin y: -12.4572 Å / Origin z: 15.16 Å
111213212223313233
T0.1444 Å20.006 Å20.0158 Å2-0.1476 Å20.0264 Å2--0.1901 Å2
L1.0928 °20.1951 °20.8973 °2-0.4998 °20.4859 °2--3.1384 °2
S0.0142 Å °0.0377 Å °0.026 Å °0.0071 Å °-0.0282 Å °-0.0025 Å °-0.0218 Å °0.0101 Å °0.0091 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 167
2X-RAY DIFFRACTION1allB56 - 131
3X-RAY DIFFRACTION1allL1 - 2
4X-RAY DIFFRACTION1allS1 - 61

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