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- PDB-10jt: CRYSTAL STRUCTURE OF KIRSTEN RAT SARCOMA G12C COMPLEXED WITH GMPP... -

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Database: PDB / ID: 10jt
TitleCRYSTAL STRUCTURE OF KIRSTEN RAT SARCOMA G12C COMPLEXED WITH GMPPNP AND COVALENTLY BOUND TO 1-[(2R,3R)-3-{[(7P)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{ [(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d] pyrimidin-4-yl](methyl)amino}-2-methylpyrrolidin-1-yl]-3-(pyrazin-2-yl)propan-1-one
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE / KRAS / GTPASE / INHIBITOR
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / LRR domain binding / response to isolation stress / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells ...response to mineralocorticoid / GMP binding / LRR domain binding / response to isolation stress / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / 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 / 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 / positive regulation of Ras protein signal transduction / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / 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 / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / 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 / liver development / GRB2 events in ERBB2 signaling / Downstream signal transduction / response to glucocorticoid / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by SCF-KIT / RAF activation / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / Signaling by RAF1 mutants / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Negative regulation of MAPK pathway / RAS processing / Regulation of RAS by GAPs / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / GDP binding / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / RAF/MAP kinase cascade / G protein activity / Ca2+ pathway / Ras protein signal transduction / mitochondrial outer membrane / Golgi membrane / focal adhesion / positive regulation of gene expression / positive regulation of cell population proliferation / GTPase activity / endoplasmic reticulum membrane / GTP binding / protein-containing complex binding
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
: / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.489 Å
AuthorsSheriff, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2026
Title: Optimization of Covalent Warhead Trajectory for KRAS G12C Active-State Inhibition.
Authors: Condakes, M.L. / Civiello, R.L. / Lakkaraju, S.K. / Sloane, J.L. / Chourb, L.S. / Downes, D.P. / Drexler, D.M. / Dzhekieva, L. / El-Samin, M. / Levins, C. / Meyer, M.J. / Mosure, K. / ...Authors: Condakes, M.L. / Civiello, R.L. / Lakkaraju, S.K. / Sloane, J.L. / Chourb, L.S. / Downes, D.P. / Drexler, D.M. / Dzhekieva, L. / El-Samin, M. / Levins, C. / Meyer, M.J. / Mosure, K. / Parker, M.F. / Qi, J. / Ruzanov, M. / Sheriff, S. / Stedman, J. / Szapiel, N. / Thompson, R.L. / Zhang, Z. / Zhuo, X. / Stewart, M.L. / Bronson, J.J.
History
DepositionJan 22, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2026Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2026Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,45010
Polymers38,9622
Non-polymers2,4888
Water3,369187
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,7255
Polymers19,4811
Non-polymers1,2444
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,7255
Polymers19,4811
Non-polymers1,2444
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.361, 39.927, 62.053
Angle α, β, γ (deg.)77.46, 81.68, 77.58
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 19480.916 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pCWOri / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, small monomeric GTPase
#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-A1C5K / 1-[(2R,3R)-3-{[(7P)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl](methyl)amino}-2-methylpyrrolidin-1-yl]-3-(pyrazin-2-yl)propan-1-one


Mass: 720.785 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C40H39F3N8O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 187 / 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: 2.01 Å3/Da / Density % sol: 38.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100 MM HEPES, pH 7.5, 30% (w/v) PEG 4000, 200 MM calcium chloride dihyrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 1.489→60.251 Å / Num. obs: 29172 / % possible obs: 66.2 % / Redundancy: 3.2 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.997 / CC1/2 anomalous: -0.046 / Rmerge(I) obs: 0.0486 / Rpim(I) all: 0.032 / Rrim(I) all: 0.0584 / AbsDiff over sigma anomalous: 0.76 / Baniso tensor eigenvalue 1: 3.7564 Å2 / Baniso tensor eigenvalue 2: 13.8658 Å2 / Baniso tensor eigenvalue 3: 0 Å2 / Baniso tensor eigenvector 1 ortho1: 0.8918 / Baniso tensor eigenvector 1 ortho2: -0.1915 / Baniso tensor eigenvector 1 ortho3: 0.41 / Baniso tensor eigenvector 2 ortho1: 0.0087 / Baniso tensor eigenvector 2 ortho2: 0.9132 / Baniso tensor eigenvector 2 ortho3: 0.4075 / Baniso tensor eigenvector 3 ortho1: -0.4524 / Baniso tensor eigenvector 3 ortho2: -0.3598 / Baniso tensor eigenvector 3 ortho3: 0.816 / Aniso diffraction limit 1: 1.476 Å / Aniso diffraction limit 2: 1.665 Å / Aniso diffraction limit 3: 1.524 Å / Aniso diffraction limit axis 1 ortho1: 0.93543 / Aniso diffraction limit axis 1 ortho2: 0.07 / Aniso diffraction limit axis 1 ortho3: -0.34642 / Aniso diffraction limit axis 2 ortho1: -0.03592 / Aniso diffraction limit axis 2 ortho2: 0.99398 / Aniso diffraction limit axis 2 ortho3: 0.10385 / Aniso diffraction limit axis 3 ortho1: 0.35157 / Aniso diffraction limit axis 3 ortho2: -0.08476 / Aniso diffraction limit axis 3 ortho3: 0.93233 / Net I/σ(I): 15.63 / Num. measured all: 93261 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 59.4 / % possible ellipsoidal: 66.2 / % possible ellipsoidal anomalous: 59.4 / % possible spherical: 58.7 / % possible spherical anomalous: 52.5 / Redundancy anomalous: 1.7 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
4.827-60.2513.310.036129.4148304830145914590.9960.1490.02380.04350.94894.899.694.899.694.81.799.6
3.798-4.8273.460.032129.9750455045145814580.997-0.120.02050.03820.74991.494.791.494.791.41.7794.7
3.266-3.7973.140.035526.0345794579145914590.996-0.1960.02350.04270.73177.985.477.985.477.91.6685.4
2.981-3.2653.280.037224.3147844784145814580.997-0.0960.02470.04480.73993.198.593.198.593.11.798.5
2.775-2.9813.40.043322.4249544954145914590.995-0.1460.02790.05170.76394.598.594.598.594.51.7498.5
2.6-2.7753.360.049220.1149064906145914590.995-0.1170.03210.05890.75781.888.181.888.181.81.7588.1
2.474-2.63.470.053318.9750655065145814580.994-0.1010.03420.06350.7594.398.194.398.194.31.7898.1
2.37-2.4743.190.056117.0846574657145914590.993-0.0420.03740.06760.75790.997.490.997.490.91.6797.4
2.284-2.373.150.060516.2445914591145814580.993-0.1260.04110.07350.77192.597.992.597.992.51.6397.9
2.195-2.2833.160.064315.6246154615145914590.993-0.0960.04240.07730.74575.686.275.686.275.61.786.2
2.129-2.1953.350.068914.748874887145914590.9930.1710.04470.08240.73493.997.493.997.493.91.7197.4
2.061-2.1293.210.082513.4346774677145814580.990.0880.05380.09880.777384.57384.5731.7484.5
2.009-2.0613.430.086213.1750095009145914590.985-0.0830.05540.10270.74194.19794.19794.11.7597
1.961-2.0093.40.107911.0849584958145814580.981-0.0970.07020.1290.7492.196.792.196.792.11.7596.7
1.903-1.9612.770.12719.0240414041145914590.9690.1090.08790.15520.8747.571.247.571.247.51.6971.2
1.852-1.9032.810.14167.6741014101145914590.968-0.1160.09780.17290.76654.471.554.471.554.41.6271.5
1.8-1.8523.080.16527.0744874487145814580.961-0.1090.1110.19980.72956.263.356.263.356.21.6563.3
1.739-1.83.140.19136.3945854585145914590.949-0.080.12660.23020.72641.947.441.947.441.91.6947.4
1.656-1.7392.920.2265.3642594259145814580.9270.0380.15610.27590.71523.429.923.429.823.31.6529.9
1.489-1.6562.90.29434.4642314231145914590.892-0.0670.20070.35780.70913.416.413.410.78.41.6416.4

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Processing

Software
NameVersionClassificationNB
autoPROCdata processing
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.94data scaling
BUSTER2.11.8refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.489→18.55 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.92 / SU R Cruickshank DPI: 0.266 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.152 / SU Rfree Blow DPI: 0.129 / SU Rfree Cruickshank DPI: 0.131
RfactorNum. reflection% reflectionSelection details
Rfree0.2268 1506 -RANDOM
Rwork0.2036 ---
obs0.2048 29149 58.6 %-
Displacement parametersBiso mean: 14.12 Å2
Baniso -1Baniso -2Baniso -3
1-0.1098 Å20.2246 Å20.3954 Å2
2--0.0778 Å20.2316 Å2
3----0.1876 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.489→18.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2702 0 166 187 3055
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015750HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0510391HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1780SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes969HARMONIC5
X-RAY DIFFRACTIONt_it2947HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion387SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5239SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.61
X-RAY DIFFRACTIONt_other_torsion16.51
LS refinement shellResolution: 1.49→1.59 Å
RfactorNum. reflection% reflection
Rfree0.2689 28 -
Rwork0.23 --
obs0.2318 583 6.6 %

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