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- PDB-9o0q: Crystal structure of GMPPNP-bound mutant MRAS in complex with MRTX1133 -

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Basic information

Entry
Database: PDB / ID: 9o0q
TitleCrystal structure of GMPPNP-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 / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Ras-related protein M-Ras
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: Ras-related protein M-Ras
B: Ras-related protein M-Ras
C: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,34529
Polymers61,4083
Non-polymers4,93726
Water8,755486
1
A: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,18510
Polymers20,4691
Non-polymers1,7169
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,41213
Polymers20,4691
Non-polymers1,94312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,7486
Polymers20,4691
Non-polymers1,2795
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.062, 110.880, 194.081
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-444-

HOH

21A-525-

HOH

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Components

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Protein , 1 types, 3 molecules ABC

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


Mass: 20469.225 Da / Num. of mol.: 3 / 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 , 7 types, 512 molecules

#2: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 3 / 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.: 3 / 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.: 3 / Source method: obtained synthetically / Formula: C33H31F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: SO4
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 486 / 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: 3.59 Å3/Da / Density % sol: 65.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 1.6M magnesium sulfate, 0.1M MES, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976292 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Feb 9, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976292 Å / Relative weight: 1
ReflectionResolution: 1.9→48.52 Å / Num. obs: 69697 / % possible obs: 99.7 % / Redundancy: 13.7 % / CC1/2: 1 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.026 / Net I/σ(I): 23.5
Reflection shellResolution: 1.9→1.94 Å / Rmerge(I) obs: 1.923 / Num. unique obs: 4414 / CC1/2: 0.802 / Rpim(I) all: 0.76

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→44.7 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2071 3557 5.11 %
Rwork0.1768 --
obs0.1783 69597 99.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→44.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4070 0 312 486 4868
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0174489
X-RAY DIFFRACTIONf_angle_d1.5096134
X-RAY DIFFRACTIONf_dihedral_angle_d17.8781801
X-RAY DIFFRACTIONf_chiral_restr0.09658
X-RAY DIFFRACTIONf_plane_restr0.014747
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.31951260.2922627X-RAY DIFFRACTION99
1.93-1.950.32731160.27572633X-RAY DIFFRACTION99
1.95-1.980.29921430.24692575X-RAY DIFFRACTION99
1.98-2.010.26341600.23722580X-RAY DIFFRACTION99
2.01-2.050.2971390.23692604X-RAY DIFFRACTION99
2.05-2.080.24851650.23162583X-RAY DIFFRACTION99
2.08-2.120.26031160.2212631X-RAY DIFFRACTION99
2.12-2.160.28281450.21812629X-RAY DIFFRACTION99
2.16-2.20.2821490.19812592X-RAY DIFFRACTION99
2.2-2.250.22721470.19262616X-RAY DIFFRACTION99
2.25-2.310.24251290.18512621X-RAY DIFFRACTION99
2.31-2.360.21911390.18272615X-RAY DIFFRACTION99
2.36-2.430.21461530.18292628X-RAY DIFFRACTION99
2.43-2.50.21621410.17832608X-RAY DIFFRACTION100
2.5-2.580.24551160.19252674X-RAY DIFFRACTION100
2.58-2.670.23371410.19852627X-RAY DIFFRACTION100
2.67-2.780.24471510.20492652X-RAY DIFFRACTION100
2.78-2.90.25181450.19552658X-RAY DIFFRACTION100
2.9-3.060.23951430.18392656X-RAY DIFFRACTION100
3.06-3.250.23791300.18512660X-RAY DIFFRACTION100
3.25-3.50.18551670.17322665X-RAY DIFFRACTION100
3.5-3.850.17231490.15242685X-RAY DIFFRACTION100
3.85-4.410.18851350.13292702X-RAY DIFFRACTION100
4.41-5.550.15771480.14362698X-RAY DIFFRACTION99
5.55-44.70.17321640.18222821X-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)
11.59711.53621.40833.70274.2084.87970.0367-0.055-0.0141-0.46530.0107-0.3422-0.27410.2991-0.02930.27720.023-0.03620.33140.03640.318417.405-26.48-61.2619
26.7464-0.88020.74560.6318-1.26542.7564-0.01580.56220.0131-0.7477-0.01810.18130.1731-0.01260.01860.5091-0.0113-0.13530.33670.03930.28437.2585-25.3643-73.3754
32.9184-0.9938-0.71550.34280.25040.19480.94650.2909-0.7979-1.8385-0.19290.67230.3427-0.3323-0.24211.24030.0851-0.340.4891-0.09210.4988-16.5356-10.4262-77.6806
46.0628-6.2039-4.30327.50255.58135.0811.48371.01030.736-1.95130.0004-1.6486-0.8018-0.1926-1.40430.79630.06510.1950.7007-0.02580.8237-6.4655-5.4299-74.6774
56.9633-1.1475-1.5978.22174.59938.05280.75940.3571-1.6409-1.2201-0.52040.99760.5454-0.29-0.15891.320.0594-0.51020.5048-0.05781.015-18.4688-19.4376-75.4
60.4397-0.626-0.41310.86460.62720.40551.01930.905-0.5774-2.0166-0.4667-0.11050.46210.29390.79051.98970.4418-0.41460.787-0.30010.4453-17.9784-6.039-88.4288
71.11680.20940.60620.08010.26330.83290.86030.9345-0.4436-0.7858-0.20320.2220.47250.0241.09382.28910.5997-0.59020.8587-0.14870.2283-24.31620.2336-89.0215
82.0105-0.4134-1.66470.06260.35331.39610.51441.1121-0.7456-1.73480.02820.71450.3145-0.24140.30711.15310.0771-0.58950.581-0.13550.6712-25.4692-3.514-80.1205
94.47115.15565.67526.11266.3428.9750.2961-0.04170.2424-1.5426-0.43361.2315-0.3147-0.93620.20370.77970.1562-0.30160.5571-0.06350.6749-28.34776.7345-75.4259
103.0873-0.0208-0.1250.14930.3591.30090.4870.0298-1.3638-1.0520.07241.10910.7311-0.3314-0.29410.8021-0.056-0.49490.4873-0.01380.8818-25.4726-8.6349-73.0153
114.1810.79171.68664.84380.824.11040.0755-0.32430.19440.35650.0017-0.2509-0.09580.5259-0.07830.1822-0.00290.01240.3218-0.02980.2011-9.89090.0423-38.8874
128.99373.8708-3.14464.5459-4.65476.3957-0.19130.4843-0.6001-0.49460.05480.02660.81480.31030.17390.3530.0520.06620.4307-0.04150.3631-5.2901-4.4096-48.9132
135.56360.80242.07089.5015-1.58352.0502-0.0353-0.27090.24530.9844-0.0034-0.6672-0.45450.56250.02380.4366-0.07830.02390.52140.0160.2717-5.57684.556-33.1235
144.21295.236-6.26126.6013-7.55069.9107-0.39360.1048-0.5058-0.7316-0.1808-0.60010.5770.53680.58780.37770.03480.0870.33230.01190.435-16.6991-16.1474-38.8785
159.29866.96677.10225.26695.36145.4811-0.044-0.3662-0.29690.9194-0.0345-0.6339-0.11780.50710.17730.4420.0021-0.04090.41610.01550.3965-14.224-12.8679-29.4323
161.50320.3935-0.29093.9954-2.33664.99750.0561-0.05320.0430.31310.16250.4729-0.0946-0.201-0.23150.21170.01370.07040.3017-0.00610.3156-23.2312-2.9713-39.6622
179.36331.1458-6.50642.6171-0.89224.49730.1120.33720.43610.04350.13210.5763-0.6751-0.5652-0.16140.28190.0387-0.00150.35020.05820.4642-28.64124.447-48.8815
184.88893.1187-2.95036.3658-3.24225.5162-0.0099-0.05980.2720.04190.03580.3072-0.46960.08480.02360.25640.0150.00360.29090.0040.2774-17.66787.787-46.314
196.7742.14620.34016.4391-4.2328.81540.144-0.42970.4440.88890.00180.4452-1-0.1747-0.23440.38490.00770.03710.2461-0.04680.3579-15.17218.5298-33.5195
204.0170.33050.59863.6678-0.58973.9096-0.05370.25280.1936-0.5325-0.00571.0681-0.1212-0.5320.11270.460.0022-0.18120.3878-0.02510.6058-3.9536-22.8365-69.1121
214.12771.2464-0.61794.253-1.07421.7947-0.0025-0.0952-0.3134-0.1435-0.01990.82380.2579-0.2580.02970.3049-0.0196-0.07810.28390.02060.40912.8611-32.6185-62.0776
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 131 through 148 )
2X-RAY DIFFRACTION2chain 'B' and (resid 149 through 178 )
3X-RAY DIFFRACTION3chain 'C' and (resid 11 through 35 )
4X-RAY DIFFRACTION4chain 'C' and (resid 36 through 47 )
5X-RAY DIFFRACTION5chain 'C' and (resid 48 through 67 )
6X-RAY DIFFRACTION6chain 'C' and (resid 68 through 96 )
7X-RAY DIFFRACTION7chain 'C' and (resid 97 through 114 )
8X-RAY DIFFRACTION8chain 'C' and (resid 115 through 130 )
9X-RAY DIFFRACTION9chain 'C' and (resid 131 through 148 )
10X-RAY DIFFRACTION10chain 'C' and (resid 149 through 178 )
11X-RAY DIFFRACTION11chain 'A' and (resid 10 through 35 )
12X-RAY DIFFRACTION12chain 'A' and (resid 36 through 47 )
13X-RAY DIFFRACTION13chain 'A' and (resid 48 through 67 )
14X-RAY DIFFRACTION14chain 'A' and (resid 68 through 75 )
15X-RAY DIFFRACTION15chain 'A' and (resid 76 through 84 )
16X-RAY DIFFRACTION16chain 'A' and (resid 85 through 130 )
17X-RAY DIFFRACTION17chain 'A' and (resid 131 through 148 )
18X-RAY DIFFRACTION18chain 'A' and (resid 149 through 163 )
19X-RAY DIFFRACTION19chain 'A' and (resid 164 through 178 )
20X-RAY DIFFRACTION20chain 'B' and (resid 11 through 75 )
21X-RAY DIFFRACTION21chain 'B' and (resid 76 through 130 )

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