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- PDB-9o0o: Crystal structure of GMPPNP-bound wild type KRAS in complex with ... -

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Basic information

Entry
Database: PDB / ID: 9o0o
TitleCrystal structure of GMPPNP-bound wild type KRAS in complex with MRTX1133
ComponentsGTPase KRas
KeywordsONCOPROTEIN / KRAS / RAS / KRAS4B
Function / homology
Function and homology information


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 / type I pneumocyte differentiation ...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 / type I pneumocyte differentiation / Rac protein signal transduction / 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 / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / skeletal muscle cell differentiation / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / glial cell proliferation / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / 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 / GRB2 events in ERBB2 signaling / Downstream signal transduction / homeostasis of number of cells within a tissue / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / 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 / FCERI mediated MAPK activation / liver development / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / RAF activation / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 KD Mutants / visual learning / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / RAS processing / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-6IC / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBonsor, D.A. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
Authors: Daniel A Bonsor / Lorenzo I Finci / Jacob R Potter / Lucy C Young / Vanessa E Wall / Ruby Goldstein de Salazar / Katie R Geis / Tyler Stephens / Joseph Finney / Dwight V Nissley / Frank ...Authors: Daniel A Bonsor / Lorenzo I Finci / Jacob R Potter / Lucy C Young / Vanessa E Wall / Ruby Goldstein de Salazar / Katie R Geis / Tyler Stephens / Joseph Finney / Dwight V Nissley / Frank McCormick / Dhirendra K Simanshu /
Abstract: RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2- ...RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2-MRAS-PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2-KRAS-PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.
History
DepositionApr 3, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,00311
Polymers19,3291
Non-polymers1,67410
Water3,333185
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)89.430, 89.430, 89.430
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number195
Space group name H-MP23
Space group name HallP223
Symmetry operation#1: x,y,z
#2: z,x,y
#3: y,z,x
#4: -y,-z,x
#5: z,-x,-y
#6: -y,z,-x
#7: -z,-x,y
#8: -z,x,-y
#9: y,-z,-x
#10: x,-y,-z
#11: -x,y,-z
#12: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-479-

HOH

21A-480-

HOH

31A-481-

HOH

41A-482-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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 BL21(DE3) (bacteria) / References: UniProt: P01116

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Non-polymers , 8 types, 195 molecules

#2: 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-6IC / 4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol / MRTX-1133


Mass: 600.633 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H31F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 185 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 3.08 Å3/Da / Density % sol: 60.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 2M lithium sulfate, 15mM magnesium chloride, 5mM spermidine, 50mM sodium cacodylate pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 26, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.9→89.43 Å / Num. obs: 19081 / % possible obs: 99.9 % / Redundancy: 6.7 % / Biso Wilson estimate: 31.55 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.062 / Net I/σ(I): 10.2
Reflection shellResolution: 1.9→1.94 Å / Rmerge(I) obs: 1.505 / Num. unique obs: 1239 / CC1/2: 0.454 / Rpim(I) all: 0.919

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→89.43 Å / SU ML: 0.2448 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.5752
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.207 891 4.67 %
Rwork0.1693 18175 -
obs0.1711 19066 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.51 Å2
Refinement stepCycle: LAST / Resolution: 1.9→89.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1342 0 107 185 1634
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081475
X-RAY DIFFRACTIONf_angle_d0.92912004
X-RAY DIFFRACTIONf_chiral_restr0.0514216
X-RAY DIFFRACTIONf_plane_restr0.0083245
X-RAY DIFFRACTIONf_dihedral_angle_d18.6634601
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-2.020.37231130.27673032X-RAY DIFFRACTION99.62
2.02-2.180.24341310.22733006X-RAY DIFFRACTION99.97
2.18-2.390.25861670.21652972X-RAY DIFFRACTION100
2.4-2.740.23631610.20213006X-RAY DIFFRACTION99.94
2.74-3.450.20451610.17523026X-RAY DIFFRACTION99.97
3.45-89.430.16921580.12113133X-RAY DIFFRACTION99.49
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)
14.927896997471.53912621904-2.711203245364.66001704894-2.775819537376.866032694840.01874218149720.37403716060.322979413142-0.2337586546310.06818181067090.0321969320509-0.548033600744-0.296198134788-0.05257179191570.2596324127610.00588981212836-0.006144302071180.2198187393430.009587283927130.198122727826-28.1942720518-12.0963177708-49.1936419873
20.744153357023-2.03916878447-2.219879992536.025204185026.664093981327.39336998533-0.08273694691510.416336233223-0.02550258615540.324918870673-0.6779777919610.5996876869010.271573884546-1.354183425610.7052459343340.4686359581790.0458672508053-0.05350034963860.730011060628-0.02849736581410.463389073507-39.569918744-14.7869730317-45.8340987282
34.975410890575.177888765791.441259797538.266025584561.203759690084.33482534869-0.386246006540.4740384826550.463760673047-0.5777177505560.4569506980590.388959559171-0.34757448433-0.0564132729623-0.09007754595770.351825480230.0138233822477-0.005396069704650.3010501269190.05099349400090.302939905851-26.3042338122-7.09514732338-54.5713669128
41.57854098916-0.00849305273506-0.8346902103092.40048196871.788555239415.640975725310.0237950605099-0.0326856739741-0.02355290955390.0008707321320760.0641865843635-0.1753121824590.03532176685020.228628741496-0.07515068640980.1847792172020.0168823187092-0.007632405525080.2021630104080.01773796959210.25186074971-22.5964354502-21.9085678436-43.3162405424
53.01796596201-2.241556536-2.66062813624.42047776280.5032302134763.91176445570.174440029627-0.5965771026950.1829635363090.190450373104-0.00561871197865-0.147706764643-0.3263663561880.226841788346-0.07491127479840.311138179574-0.0604718697601-0.006581052397340.2695007812240.0004251314238140.304943692279-20.3007992819-12.0084901252-34.8482912106
67.69981993835-1.27778146932-3.100231101882.802413711862.099740010757.10612425371-0.0156665321570.09073714258510.367117898592-0.1419274151340.236221570813-0.155737450486-0.4163496303430.359633832984-0.3494223847270.349972254263-0.0395415561840.0313133358080.2323855528910.02666394735630.308401494388-16.9916874386-7.27135606637-48.5390253697
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 0 through 25 )0 - 251 - 26
22chain 'A' and (resid 26 through 37 )26 - 3727 - 38
33chain 'A' and (resid 38 through 57 )38 - 5739 - 58
44chain 'A' and (resid 58 through 126 )58 - 12659 - 127
55chain 'A' and (resid 127 through 151 )127 - 151128 - 152
66chain 'A' and (resid 152 through 168 )152 - 168153 - 169

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