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- PDB-9o0p: Crystal structure of GDP-bound mutant MRAS in complex with MRTX1133 -

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Basic information

Entry
Database: PDB / ID: 9o0p
TitleCrystal structure of GDP-bound mutant MRAS in complex with MRTX1133
ComponentsRas-related protein M-Ras
KeywordsONCOPROTEIN / MRAS / RAS
Function / homology
Function and homology information


protein phosphatase type 1 complex / GTP-dependent protein binding / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / cellular response to leukemia inhibitory factor / small monomeric GTPase / RAF activation / GDP binding / G protein activity / actin cytoskeleton organization ...protein phosphatase type 1 complex / GTP-dependent protein binding / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / cellular response to leukemia inhibitory factor / small monomeric GTPase / RAF activation / GDP binding / G protein activity / actin cytoskeleton organization / Ras protein signal transduction / GTPase activity / GTP binding / plasma membrane
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 / GUANOSINE-5'-DIPHOSPHATE / Ras-related protein M-Ras
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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: Ras-related protein M-Ras
B: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0868
Polymers40,9382
Non-polymers2,1476
Water6,612367
1
A: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,5735
Polymers20,4691
Non-polymers1,1044
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,5133
Polymers20,4691
Non-polymers1,0442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.999, 62.606, 140.857
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Ras-related protein M-Ras / Ras-related protein R-Ras3


Mass: 20469.225 Da / Num. of mol.: 2 / Mutation: F74Y, R105H, F106Y, L109Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MRAS, RRAS3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O14807, small monomeric GTPase

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Non-polymers , 5 types, 373 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*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.: 2 / Source method: obtained synthetically / Formula: C33H31F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 367 / 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: 2.15 Å3/Da / Density % sol: 42.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20% PEG 3350, 0.2M ammonium fluoride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.81515 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 23, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.81515 Å / Relative weight: 1
ReflectionResolution: 1.5→62.61 Å / Num. obs: 57604 / % possible obs: 99.8 % / Redundancy: 13.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.034 / Net I/σ(I): 15.5
Reflection shellResolution: 1.5→1.53 Å / Rmerge(I) obs: 1.676 / Num. unique obs: 2778 / CC1/2: 0.666 / Rpim(I) all: 0.685

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→57.21 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2214 2899 5.04 %
Rwork0.1946 --
obs0.1961 57503 99.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.5→57.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2735 0 146 367 3248
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0133021
X-RAY DIFFRACTIONf_angle_d1.4124134
X-RAY DIFFRACTIONf_dihedral_angle_d19.981191
X-RAY DIFFRACTIONf_chiral_restr0.104447
X-RAY DIFFRACTIONf_plane_restr0.012516
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.520.33671300.29132529X-RAY DIFFRACTION98
1.52-1.550.28821410.27372562X-RAY DIFFRACTION100
1.55-1.580.25871280.25222574X-RAY DIFFRACTION100
1.58-1.610.29961430.25372572X-RAY DIFFRACTION100
1.61-1.640.2991450.24962517X-RAY DIFFRACTION99
1.64-1.680.28461230.23962575X-RAY DIFFRACTION100
1.68-1.720.27381490.23232551X-RAY DIFFRACTION100
1.72-1.760.26841340.23842584X-RAY DIFFRACTION100
1.76-1.810.29331170.22912621X-RAY DIFFRACTION100
1.81-1.860.25391400.22792546X-RAY DIFFRACTION100
1.86-1.920.25531380.21622594X-RAY DIFFRACTION100
1.92-1.990.24421400.20322590X-RAY DIFFRACTION100
1.99-2.070.24511220.20562620X-RAY DIFFRACTION100
2.07-2.160.23461180.21032610X-RAY DIFFRACTION100
2.16-2.280.25681650.20842559X-RAY DIFFRACTION100
2.28-2.420.22621380.19652627X-RAY DIFFRACTION100
2.42-2.610.2311380.19482637X-RAY DIFFRACTION100
2.61-2.870.19931470.19372633X-RAY DIFFRACTION100
2.87-3.280.22061520.17942586X-RAY DIFFRACTION99
3.28-4.140.19531330.16132701X-RAY DIFFRACTION100
4.14-57.210.17211580.17292816X-RAY DIFFRACTION100
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)
12.6248-2.16861.08083.852-0.22940.8911-0.0781-0.2162-0.11110.38850.15440.3024-0.0507-0.2561-0.0930.1336-0.00240.03410.2016-0.00950.1553-20.5012-0.27268.1261
24.60311.538-1.57921.3033-2.00123.29690.0195-0.52920.52160.52860.00141.3008-0.3583-1.0031-0.05340.3510.04340.13090.5095-0.08030.623-23.75537.931214.3463
37.28775.1115-0.37293.7201-0.62472.47220.3501-0.2901-0.20570.6413-0.16530.19780.2171-0.2336-0.11940.2158-0.03460.02050.2230.01340.1853-22.7946-7.260414.3078
42.9965-0.02420.1572.09780.35241.43450.11410.1737-0.0013-0.0754-0.0469-0.11040.00460.09-0.04750.05790.00810.01580.1418-0.00610.1083-11.73441.1521.1126
53.2627-0.8157-0.28712.1794-0.10852.00490.17310.5437-0.0635-0.3904-0.19660.256-0.0689-0.11360.02690.16170.0369-0.04730.2533-0.03290.1858-25.24320.3076-7.7218
66.6460.97520.13785.1498-1.2457.26840.11230.218-0.6016-0.08710.0150.30550.3827-0.3037-0.02360.1033-0.04360.01360.1538-0.01470.2354-22.5317-11.28194.646
71.044-0.35770.47592.6965-0.10393.2605-0.024-0.01640.00950.5266-0.01870.0833-0.1801-0.2892-0.05740.54330.04120.00140.2093-0.02190.108-14.57394.458128.1782
80.5801-0.15980.57651.3599-0.23213.0919-0.0097-0.23020.010.67240.15740.14110.1838-0.2258-0.04230.36380.02140.0690.2973-0.01910.2318-17.46661.721523.1414
98.66093.4507-2.49649.69051.85618.65330.02580.8280.5465-0.6413-0.20140.4361-1.00510.08990.0580.75610.0309-0.13440.42720.00080.4176-3.625115.430521.9548
100.7360.0544-0.54450.13060.30431.66970.22280.05970.09330.3116-0.0832-0.0705-0.27220.0672-0.10050.78770.0098-0.02610.2421-0.0210.2044-10.016313.231933.9711
110.30240.0647-0.49980.10820.13061.423-0.0415-0.203-0.00370.35570.055-0.12850.12950.25220.07230.86350.0355-0.08010.32070.01680.1996-6.73842.957143.6347
122.12220.4716-1.43090.19290.3536.04710.1081-0.00980.16070.19320.04320.0901-0.2656-0.51240.18460.69830.04190.13630.3324-0.02010.1714-22.08034.716536.163
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 33 )
2X-RAY DIFFRACTION2chain 'A' and (resid 34 through 47 )
3X-RAY DIFFRACTION3chain 'A' and (resid 48 through 67 )
4X-RAY DIFFRACTION4chain 'A' and (resid 68 through 130 )
5X-RAY DIFFRACTION5chain 'A' and (resid 131 through 163 )
6X-RAY DIFFRACTION6chain 'A' and (resid 164 through 178 )
7X-RAY DIFFRACTION7chain 'B' and (resid 10 through 33 )
8X-RAY DIFFRACTION8chain 'B' and (resid 34 through 67 )
9X-RAY DIFFRACTION9chain 'B' and (resid 68 through 77 )
10X-RAY DIFFRACTION10chain 'B' and (resid 78 through 130 )
11X-RAY DIFFRACTION11chain 'B' and (resid 131 through 163 )
12X-RAY DIFFRACTION12chain 'B' and (resid 164 through 178 )

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