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- PDB-12lc: Crystal structure of human KRAS G12C covalently bound to AM-8719 -

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Basic information

Entry
Database: PDB / ID: 12lc
TitleCrystal structure of human KRAS G12C covalently bound to AM-8719
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / Inhibitor / GTPase
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 / Signaling by SCF-KIT / RAF activation / Constitutive Signaling by EGFRvIII / 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 / positive regulation of cellular senescence / Signaling by BRAF and RAF1 fusions / 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: 1.9 Å
AuthorsMohr, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2026
Title: Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel, CNS-Penetrant KRAS G12C Inhibitor
Authors: Rast, S. / Morgan-Fisher, M. / Blomquist, S.D. / Cadahia, J.P. / Cowland, S. / Franch, T. / Glibstrup, E. / Gouliaev, A. / Haahr Hansen, M. / Kontijevskis, A. / Kronborg, T. / Moretti, L. / ...Authors: Rast, S. / Morgan-Fisher, M. / Blomquist, S.D. / Cadahia, J.P. / Cowland, S. / Franch, T. / Glibstrup, E. / Gouliaev, A. / Haahr Hansen, M. / Kontijevskis, A. / Kronborg, T. / Moretti, L. / Nadali, A. / Nielsen, S. / Leth-Petersen, S. / Rabe, M. / Alafate, A. / Allen, J.R. / Banerjee, A. / Booker, S.K. / Butler, J.R. / Hot, I. / Huang, D. / Kaller, M.R. / Kapoor, R. / Liu, Q. / Lopez, P. / Ma, V. / Manoni, F. / Medina, J.M. / Pickrell, A.J. / Wang, H.L. / Xie, J. / Zhang, W. / Mohr, C. / Chen, K. / Saiki, A.Y. / Wang, P. / Leavitt, M. / Rex, K. / Zhong, G. / Zou, L. / Lade, J. / Dahal, U.P. / Farhan, N. / Agarwal, P. / Zandkarimi, B. / Zhu, K. / Husemoen, G. / Tamayo, N.A. / Lanman, B.A.
History
DepositionApr 10, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1244
Polymers21,0391
Non-polymers1,0853
Water1,910106
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)94.340, 94.340, 119.531
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

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


Mass: 21038.613 Da / Num. of mol.: 1 / Mutation: G12C, C51S, C80L, C118S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Variant: VAR_006839 G12C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-A1DI7 / 1-(4-{(2R,3R)-1-[6-{4-[2-(3-methoxyoxetan-3-yl)-4-methylpyridin-3-yl]piperidin-1-yl}-2-(trifluoromethyl)pyrimidin-4-yl]-2-methylazetidin-3-yl}piperazin-1-yl)propan-1-one / AM-8719, bound form


Mass: 617.705 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H42F3N7O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 2.43 Å3/Da / Density % sol: 49.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 200mM lithium sulfate, 100mM TRIS, 30% PEG 4000, 5mM magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 1.1807 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 18, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1807 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 31218 / % possible obs: 99.8 % / Redundancy: 6.85 % / CC1/2: 0.999 / Rmerge(I) obs: 0.097 / Net I/σ(I): 14.59
Reflection shellResolution: 1.9→2.02 Å / Redundancy: 6.53 % / Rmerge(I) obs: 1.95 / Mean I/σ(I) obs: 0.91 / Num. unique obs: 5006 / CC1/2: 0.407 / % possible all: 99.1

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Processing

Software
NameVersionClassification
XDSv2022data reduction
XDSv2022data scaling
MOLREPphasing
REFMAC5.8.0267refinement
Coot0.8.9.1model building
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→29.9 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.914 / SU B: 4.692 / SU ML: 0.125 / Cross valid method: THROUGHOUT / ESU R: 0.168 / ESU R Free: 0.16
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26416 766 4.7 %RANDOM
Rwork0.21508 ---
obs0.21735 15557 99.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.294 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0.01 Å2-0 Å2
2---0.01 Å2-0 Å2
3---0.04 Å2
Refinement stepCycle: 1 / Resolution: 1.9→29.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1355 0 73 106 1534
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0131462
X-RAY DIFFRACTIONr_bond_other_d0.0020.0151359
X-RAY DIFFRACTIONr_angle_refined_deg1.2991.7341977
X-RAY DIFFRACTIONr_angle_other_deg1.0881.6243079
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0535168
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.17222.65879
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.01615255
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7741510
X-RAY DIFFRACTIONr_chiral_restr0.040.2192
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021600
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02316
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0043.129675
X-RAY DIFFRACTIONr_mcbond_other1.0043.127674
X-RAY DIFFRACTIONr_mcangle_it1.8134.686842
X-RAY DIFFRACTIONr_mcangle_other1.8124.688843
X-RAY DIFFRACTIONr_scbond_it0.9143.295787
X-RAY DIFFRACTIONr_scbond_other0.9133.295788
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.6044.8861132
X-RAY DIFFRACTIONr_long_range_B_refined3.6136.6981651
X-RAY DIFFRACTIONr_long_range_B_other3.46636.4331626
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.901→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.484 39 -
Rwork0.452 1134 -
obs--98.82 %

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