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- PDB-8v39: Crystal structure of active KRAS-G12C (GMPPNP-bound) in complex w... -

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Basic information

Entry
Database: PDB / ID: 8v39
TitleCrystal structure of active KRAS-G12C (GMPPNP-bound) in complex with BBO-8520
ComponentsGTPase KRas
KeywordsONCOPROTEIN/INHIBITOR / KRAS / RAS / K-ras / KRAS4b / inhibitor / BBO8520 / BBO-8520 / BBO / TheRas / BridgeBio / oncoprotein / ONCOPROTEIN-INHIBITOR complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / 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 / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / 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 / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
Similarity search - Function
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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / : / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsChan, A.H. / Ashraf, M. / 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: Cancer Discov / Year: 2025
Title: Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C.
Authors: Maciag, A.E. / Stice, J.P. / Wang, B. / Sharma, A.K. / Chan, A.H. / Lin, K. / Singh, D. / Dyba, M. / Yang, Y. / Setoodeh, S. / Smith, B.P. / Ju, J.H. / Jeknic, S. / Rabara, D. / Zhang, Z. / ...Authors: Maciag, A.E. / Stice, J.P. / Wang, B. / Sharma, A.K. / Chan, A.H. / Lin, K. / Singh, D. / Dyba, M. / Yang, Y. / Setoodeh, S. / Smith, B.P. / Ju, J.H. / Jeknic, S. / Rabara, D. / Zhang, Z. / Larsen, E.K. / Esposito, D. / Denson, J.P. / Ranieri, M. / Meynardie, M. / Mehdizadeh, S. / Alexander, P.A. / Abreu Blanco, M. / Turner, D.M. / Xu, R. / Lightstone, F.C. / Wong, K.K. / Stephen, A.G. / Wang, K. / Simanshu, D.K. / Sinkevicius, K.W. / Nissley, D.V. / Wallace, E. / McCormick, F. / Beltran, P.J.
History
DepositionNov 27, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,91112
Polymers58,0773
Non-polymers3,8359
Water5,459303
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6374
Polymers19,3591
Non-polymers1,2783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6374
Polymers19,3591
Non-polymers1,2783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6374
Polymers19,3591
Non-polymers1,2783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)115.960, 115.960, 180.500
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-333-

HOH

21A-397-

HOH

31A-407-

HOH

41A-414-

HOH

51B-341-

HOH

61C-314-

HOH

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Components

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


Mass: 19358.836 Da / Num. of mol.: 3 / Mutation: G12C C118S
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: 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-Y8N / BBO-8520 (bound form) / (4P)-2-amino-4-{4-[(2S,5R)-2,5-dimethyl-4-propanoylpiperazin-1-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-6-(trifluoromethyl)quinazolin-7-yl}-7-fluoro-1-benzothiophene-3-carbonitrile


Mass: 731.754 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C35H35F6N7O2S / Details: Reacted form present. / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 303 / 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: 3.02 Å3/Da / Density % sol: 59.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 56.36 mM NaH2PO4, 1343 mM K2HPO4

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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 EIGER2 X 16M / Detector: PIXEL / Date: Nov 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.1→48.78 Å / Num. obs: 42427 / % possible obs: 99.8 % / Redundancy: 7.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.086 / Rrim(I) all: 0.092 / Net I/σ(I): 12.7
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.1-2.150.91930710.8410.9931
2.15-2.210.70630000.9350.7551
2.21-2.280.58629280.9560.6261
2.28-2.350.45928260.9720.491
2.35-2.420.36127550.9830.3851
2.42-2.510.30526810.9890.3261
2.51-2.60.23725820.9930.2531
2.6-2.710.20924950.9940.2241
2.71-2.830.16124020.9960.1731
2.83-2.970.12422920.9980.1331
2.97-3.130.09421740.9980.1021
3.13-3.320.07220750.9990.0771
3.32-3.550.05319610.9990.0571
3.55-3.830.04618460.9990.0491
3.83-4.20.039169410.0421
4.2-4.70.034154510.0371
4.7-5.420.03113860.9990.0341
5.42-6.640.034119010.0371
6.64-9.390.0289530.9990.031
9.39-48.780.0285710.9990.0311

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→48.78 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 38.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3122 4221 10.02 %
Rwork0.2655 --
obs0.2701 42116 99.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→48.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4010 0 252 303 4565
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094346
X-RAY DIFFRACTIONf_angle_d0.9935929
X-RAY DIFFRACTIONf_dihedral_angle_d15.1141665
X-RAY DIFFRACTIONf_chiral_restr0.056651
X-RAY DIFFRACTIONf_plane_restr0.009743
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.120.35761380.33451242X-RAY DIFFRACTION99
2.12-2.150.38831400.32731253X-RAY DIFFRACTION99
2.15-2.170.29781350.29951228X-RAY DIFFRACTION100
2.18-2.20.38151380.29051234X-RAY DIFFRACTION99
2.2-2.230.28891410.28311269X-RAY DIFFRACTION100
2.23-2.260.32631370.27281229X-RAY DIFFRACTION100
2.26-2.290.33271390.27091244X-RAY DIFFRACTION100
2.29-2.330.36731400.26821258X-RAY DIFFRACTION100
2.33-2.370.33061390.26751245X-RAY DIFFRACTION100
2.37-2.40.29791400.24931248X-RAY DIFFRACTION99
2.4-2.450.25811360.24641243X-RAY DIFFRACTION100
2.45-2.490.29671410.25531255X-RAY DIFFRACTION99
2.49-2.540.36541390.26391241X-RAY DIFFRACTION99
2.54-2.590.31400.25291248X-RAY DIFFRACTION99
2.59-2.650.28091410.2671267X-RAY DIFFRACTION99
2.65-2.710.28481380.27121245X-RAY DIFFRACTION99
2.71-2.770.29261390.27161253X-RAY DIFFRACTION100
2.77-2.850.30841380.26251254X-RAY DIFFRACTION99
2.85-2.930.28931410.24521259X-RAY DIFFRACTION99
2.93-3.030.28941410.25121258X-RAY DIFFRACTION99
3.03-3.140.33381430.26021286X-RAY DIFFRACTION99
3.14-3.260.3071390.24461254X-RAY DIFFRACTION100
3.26-3.410.26981430.24661281X-RAY DIFFRACTION99
3.41-3.590.25021400.22641265X-RAY DIFFRACTION99
3.59-3.820.38081420.24161275X-RAY DIFFRACTION99
3.82-4.110.31961430.25071293X-RAY DIFFRACTION100
4.11-4.520.29121440.23531301X-RAY DIFFRACTION99
4.52-5.180.28231450.25881309X-RAY DIFFRACTION99
5.18-6.520.27991490.31111339X-RAY DIFFRACTION99
6.52-48.780.43141520.34351319X-RAY DIFFRACTION91
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)
12.013-0.4727-0.08762.7074-0.42282.04930.0680.11330.24270.0116-0.1328-0.0432-0.3703-0.13520.06050.27460.0456-0.020.10490.00780.1133-2.517118.2366-6.1901
21.1116-0.0910.06683.02310.27071.57020.0336-0.03030.07520.0093-0.0883-0.2040.04440.03870.03420.4170.0667-0.01190.24990.01420.3852.387648.7735-6.1355
31.80370.5497-0.57951.70390.19481.6208-0.0688-0.06980.0419-0.2659-0.15830.77720.5717-0.68580.13680.6-0.2529-0.03110.6927-0.19860.7502-14.579455.666723.8592
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 0 through 201)
2X-RAY DIFFRACTION2(chain 'B' and resid 0 through 201)
3X-RAY DIFFRACTION3(chain 'C' and resid 0 through 201)

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