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- PDB-9kpn: Crystal structure of KRAS-G12C in complex with Compound 20 (JAB-20) -

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Basic information

Entry
Database: PDB / ID: 9kpn
TitleCrystal structure of KRAS-G12C in complex with Compound 20 (JAB-20)
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN / KRAS4B / G12C / GTPase / inhibitor
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) / Erythropoietin activates RAS / Signaling by FGFR4 in disease / 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 / positive regulation of glial cell proliferation / Tie2 Signaling / 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 / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / 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 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: 1.29 Å
AuthorsLi, S. / Dang, C. / Fan, X. / Zhang, W. / Wang, P. / Qian, D. / Wang, Y. / Li, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS G12C.
Authors: Li, A. / Li, S. / Wang, P. / Dang, C. / Fan, X. / Chen, M. / Liu, D. / Li, F. / Liu, H. / Zhang, W. / Wang, Y. / Wang, Y.
History
DepositionNov 23, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)44,6608
Polymers42,4342
Non-polymers2,2266
Water7,278404
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3605
Polymers21,2171
Non-polymers1,1434
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area720 Å2
ΔGint-8 kcal/mol
Surface area8290 Å2
MethodPISA
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3003
Polymers21,2171
Non-polymers1,0832
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area640 Å2
ΔGint-7 kcal/mol
Surface area8630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)34.440, 78.600, 109.580
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Components on special symmetry positions
IDModelComponents
11A-480-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: MET / Beg label comp-ID: MET / End auth comp-ID: LYS / End label comp-ID: LYS / Auth seq-ID: 1 - 165 / Label seq-ID: 16 - 180

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 21216.910 Da / Num. of mol.: 2 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, small monomeric GTPase

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Non-polymers , 5 types, 410 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 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-A1L6B / 7-[2-azanyl-3,4,5,6-tetrakis(fluoranyl)phenyl]-6-chloranyl-1-(4-methyl-2-propan-2-yl-pyridin-3-yl)-2-oxidanylidene-4-(4-prop-2-enoylpiperazin-1-yl)-1,8-naphthyridine-3-carbonitrile


Mass: 640.030 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H26ClF4N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / 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.: 404 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 1.92 Å3/Da / Density % sol: 29.62 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.3 / Details: 0.1 M Sodium cacodylate, pH 5.3, 25% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 6, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.29→44.954 Å / Num. obs: 75841 / % possible obs: 99.9 % / Redundancy: 11.7 % / CC1/2: 0.987 / Rmerge(I) obs: 0.182 / Net I/σ(I): 11
Reflection shellResolution: 1.29→1.31 Å / Rmerge(I) obs: 0.222 / Mean I/σ(I) obs: 5.4 / Num. unique obs: 3898 / CC1/2: 0.962

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.29→44.954 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.952 / SU B: 0.691 / SU ML: 0.031 / Cross valid method: THROUGHOUT / ESU R: 0.054 / ESU R Free: 0.055
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1931 3733 4.927 %
Rwork0.1726 72037 -
all0.174 --
obs-75770 99.816 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 10.434 Å2
Baniso -1Baniso -2Baniso -3
1--0.345 Å2-0 Å2-0 Å2
2---0.111 Å20 Å2
3---0.456 Å2
Refinement stepCycle: LAST / Resolution: 1.29→44.954 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2662 0 148 404 3214
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0133015
X-RAY DIFFRACTIONr_bond_other_d0.0010.0152765
X-RAY DIFFRACTIONr_angle_refined_deg1.5161.7334109
X-RAY DIFFRACTIONr_angle_other_deg1.3981.6296387
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9265362
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.34322.47166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.24715531
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9891522
X-RAY DIFFRACTIONr_chiral_restr0.0640.2385
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023445
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02679
X-RAY DIFFRACTIONr_nbd_refined0.2120.2598
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1790.22744
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21437
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.21371
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1590.2305
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.2180.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2480.229
X-RAY DIFFRACTIONr_nbd_other0.2190.2116
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.130.254
X-RAY DIFFRACTIONr_mcbond_it0.660.9471398
X-RAY DIFFRACTIONr_mcbond_other0.660.9461397
X-RAY DIFFRACTIONr_mcangle_it1.1141.4191763
X-RAY DIFFRACTIONr_mcangle_other1.1141.4191764
X-RAY DIFFRACTIONr_scbond_it0.9251.0941617
X-RAY DIFFRACTIONr_scbond_other0.9231.0951613
X-RAY DIFFRACTIONr_scangle_it1.4941.5922341
X-RAY DIFFRACTIONr_scangle_other1.4931.5922342
X-RAY DIFFRACTIONr_lrange_it4.18212.2793636
X-RAY DIFFRACTIONr_lrange_other4.03211.7173537
X-RAY DIFFRACTIONr_ncsr_local_group_10.1430.055143
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.143480.05008
12BX-RAY DIFFRACTIONLocal ncs0.143480.05008
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.29-1.3230.2122720.19452080.19555720.9480.95298.34890.194
1.323-1.360.22550.19450670.19453390.9510.94999.68160.194
1.36-1.3990.2032580.18549650.18652250.9490.95199.96170.185
1.399-1.4420.1912510.18548920.18551430.9530.9531000.185
1.442-1.4890.1912400.1847360.18149760.9550.9541000.18
1.489-1.5420.1812180.17345340.17347530.9580.9699.9790.173
1.542-1.60.212060.17344280.17546350.9460.95699.97840.173
1.6-1.6650.2162170.17342690.17544870.940.95599.97770.173
1.665-1.7390.1992030.17940850.1842880.9480.9551000.179
1.739-1.8240.1842100.17139040.17141150.9550.96299.97570.171
1.824-1.9220.1812210.16936750.1738960.9610.9631000.169
1.922-2.0380.192030.16435200.16537240.9620.96599.97310.164
2.038-2.1790.1881870.16433080.16534950.9580.9661000.164
2.179-2.3530.1771510.16331010.16432530.960.96399.96930.163
2.353-2.5770.1771500.16428720.16530220.960.9621000.164
2.577-2.880.1741380.16626390.16627780.9610.96699.9640.166
2.88-3.3230.1871130.16423090.16524230.9620.96799.95870.164
3.323-4.0640.1981100.15219860.15520970.960.9799.95230.152
4.064-5.7240.2800.18315890.18416700.9650.96799.94010.183
5.724-44.9540.29500.2399410.2429940.9530.95799.69820.239

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