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- PDB-7lc2: Crystal Structure of KRAS4b-Q61R (GMPPNP-bound) in complex with t... -

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Basic information

Entry
Database: PDB / ID: 7lc2
TitleCrystal Structure of KRAS4b-Q61R (GMPPNP-bound) in complex with the RAS-binding domain (RBD) of SIN1
Components
  • GTPase KRas
  • Target of rapamycin complex 2 subunit MAPKAP1
KeywordsONCOPROTEIN / Hydrolase / KRAS / RAS / K-RAS / Small GTPase / GMPPNP / GppNHp MAPKAP1 / mTORC2 / SIN1 / RBD
Function / homology
Function and homology information


TORC2 signaling / TORC2 complex / regulation of cellular response to oxidative stress / phosphatidic acid binding / negative regulation of Ras protein signal transduction / serine/threonine protein kinase complex / phosphatidylinositol-3,4-bisphosphate binding / phosphatidylinositol-3,5-bisphosphate binding / response to mineralocorticoid / GMP binding ...TORC2 signaling / TORC2 complex / regulation of cellular response to oxidative stress / phosphatidic acid binding / negative regulation of Ras protein signal transduction / serine/threonine protein kinase complex / phosphatidylinositol-3,4-bisphosphate binding / phosphatidylinositol-3,5-bisphosphate binding / response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / type I pneumocyte differentiation / Rac protein signal transduction / phosphatidylinositol-3,4,5-trisphosphate binding / 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 / SOS-mediated signalling / Activated NTRK3 signals through RAS / CD28 dependent PI3K/Akt signaling / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / enzyme-substrate adaptor activity / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / cellular response to nutrient levels / 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 / striated muscle cell differentiation / Signaling by FGFR2 in disease / phosphatidylinositol-4,5-bisphosphate binding / cytoskeleton organization / 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 / substantia nigra development / CD209 (DC-SIGN) signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / negative regulation of insulin 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 / VEGFR2 mediated cell proliferation / small monomeric GTPase / VEGFR2 mediated vascular permeability / FCERI mediated MAPK activation / liver development / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants
Similarity search - Function
Sin1, N-terminal / Stress-activated map kinase interacting protein 1 (SIN1) / TORC2 component Sin1/Avo1 / SAPK-interacting protein 1, Pleckstrin-homology domain / Sin1, middle CRIM domain / SAPK-interacting protein 1 (Sin1), middle CRIM domain / SAPK-interacting protein 1 (Sin1), Pleckstrin-homology / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases ...Sin1, N-terminal / Stress-activated map kinase interacting protein 1 (SIN1) / TORC2 component Sin1/Avo1 / SAPK-interacting protein 1, Pleckstrin-homology domain / Sin1, middle CRIM domain / SAPK-interacting protein 1 (Sin1), middle CRIM domain / SAPK-interacting protein 1 (Sin1), Pleckstrin-homology / 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 / PH-like domain superfamily / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas / Target of rapamycin complex 2 subunit MAPKAP1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsDharmaiah, S. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2021
Title: RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity.
Authors: Castel, P. / Dharmaiah, S. / Sale, M.J. / Messing, S. / Rizzuto, G. / Cuevas-Navarro, A. / Cheng, A. / Trnka, M.J. / Urisman, A. / Esposito, D. / Simanshu, D.K. / McCormick, F.
History
DepositionJan 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 28, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.pdbx_database_id_DOI ..._citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Nov 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

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
D: Target of rapamycin complex 2 subunit MAPKAP1
E: Target of rapamycin complex 2 subunit MAPKAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,8328
Polymers58,7394
Non-polymers1,0934
Water41423
1
A: GTPase KRas
E: Target of rapamycin complex 2 subunit MAPKAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,9164
Polymers29,3702
Non-polymers5472
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
D: Target of rapamycin complex 2 subunit MAPKAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,9164
Polymers29,3702
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)150.000, 45.640, 91.780
Angle α, β, γ (deg.)90.000, 119.520, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 19545.459 Da / Num. of mol.: 2 / 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 Target of rapamycin complex 2 subunit MAPKAP1 / TORC2 subunit MAPKAP1 / Mitogen-activated protein kinase 2-associated protein 1 / Stress-activated ...TORC2 subunit MAPKAP1 / Mitogen-activated protein kinase 2-associated protein 1 / Stress-activated map kinase-interacting protein 1 / mSIN1


Mass: 9824.110 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAP1, MIP1, SIN1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BPZ7
#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O
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: 2.34 Å3/Da / Density % sol: 47.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 100mM MMT buffer (DL-malic acid, MES and Tris base in 1:2:2 ratio) pH 5, 25% PEG (polyethylene glycol) 1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.7→45.47 Å / Num. obs: 15142 / % possible obs: 99.5 % / Redundancy: 6.635 % / Biso Wilson estimate: 74.424 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.102 / Rrim(I) all: 0.111 / Χ2: 0.877 / Net I/σ(I): 11.57 / Num. measured all: 100465
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
2.7-2.856.9181.0062.2315449224022330.7421.08899.7
2.85-3.026.5060.6333.5213200203520290.8770.68999.7
3.02-3.236.4940.3565.8712696196119550.9590.38799.7
3.23-3.496.9180.2149.6412625183418250.9820.23299.5
3.49-3.826.7250.13912.9211163166916600.990.1599.5
3.82-4.276.6360.09717.5810060152615160.9940.10599.3
4.27-4.936.320.07420.838501135213450.9950.0899.5
4.93-6.046.8190.07521.527890116511570.9960.08199.3
6.04-8.546.4030.06721.9357699119010.9960.07398.9
8.54-45.475.9730.04925.4531125285210.9980.05398.7

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VJJ

6vjj


Resolution: 2.7→45.47 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2874 1514 10 %
Rwork0.2385 13624 -
obs0.2433 15138 99.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 155.46 Å2 / Biso mean: 85.179 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.7→45.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3744 0 66 23 3833
Biso mean--71.1 81.71 -
Num. residues----482
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.7-2.790.37951340.325212061340
2.79-2.890.38631360.30412261362
2.89-30.34291370.304812291366
3-3.140.3181370.29212291366
3.14-3.30.30791360.252212271363
3.3-3.510.32451380.251312401378
3.51-3.780.29171370.239712311368
3.78-4.160.27111370.226212391376
4.16-4.760.2731370.204712291366
4.76-60.28491400.243312671407
6-45.470.25351450.220913011446
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)
16.34270.24940.97015.9519-0.02675.4030.06040.4873-0.04040.0103-0.0603-0.2574-0.0369-0.09450.01390.41020.06070.00080.4365-0.03030.39144.144243.228914.8046
26.402-0.3886-1.17774.5011.39234.91860.01420.8755-0.6235-0.3478-0.39620.08530.20840.10180.33150.54890.16960.06690.7672-0.0530.61185.454734.357316.98
36.12741.73172.56364.33941.66879.3747-0.14220.24290.0839-0.073-0.00540.0813-0.5065-0.32180.070.53120.04870.08430.4559-0.00780.60772.319148.296735.9427
49.15720.3638-1.87614.7191-0.32484.7064-0.1138-0.4512-0.89190.5308-0.14670.27530.18730.16910.17150.8316-0.00330.04010.4132-0.02190.624835.760229.193936.3394
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 0 through 166)A0 - 166
2X-RAY DIFFRACTION2(chain 'B' and resid 1 through 166)B1 - 166
3X-RAY DIFFRACTION3(chain 'D' and resid 278 through 358)D278 - 358
4X-RAY DIFFRACTION4(chain 'E' and resid 278 through 355)E278 - 355

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