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- PDB-9gbj: KRAS G12D in complex with covalent inhibitor -

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Basic information

Entry
Database: PDB / ID: 9gbj
TitleKRAS G12D in complex with covalent inhibitor
ComponentsGTPase KRas
KeywordsHYDROLASE / Covalent inhibitor / irreversible inhibitor / aspartic acid / KRAS / carbodiimide
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
: / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.712 Å
AuthorsSirocchi, L.S. / Zak, K.M. / Wilding, B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Am.Chem.Soc. / Year: 2025
Title: Discovery of Carbodiimide Warheads to Selectively and Covalently Target Aspartic Acid in KRAS G12D .
Authors: Sirocchi, L.S. / Scharnweber, M. / Oberndorfer, S. / Siszler, G. / Zak, K.M. / Rumpel, K. / Neumuller, R.A. / Wilding, B.
History
DepositionJul 31, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 30, 2025Provider: repository / Type: Initial release
Revision 1.1May 21, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID

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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)20,5154
Polymers19,3711
Non-polymers1,1443
Water4,684260
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-19 kcal/mol
Surface area8480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.185, 40.452, 55.746
Angle α, β, γ (deg.)90, 90, 90
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 19370.781 Da / Num. of mol.: 1
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
#2: 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
#3: Chemical ChemComp-A1IJ7 / 1-[(3S)-1-[2-[5-[(4S)-2-azanyl-3-cyano-4-methyl-6,7-dihydro-5H-1-benzothiophen-4-yl]-1,2,4-oxadiazol-3-yl]-6-[(1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethoxy]pyrimidin-4-yl]pyrrolidin-3-yl]-3-[1-(methoxymethyl)cyclopropyl]urea


Mass: 676.832 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H44N10O4S / 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 260 / 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: 2.54 Å3/Da / Density % sol: 51.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.2 mM MgCl2, 15% PEG 2000, 100 mM sodium acetate pH 4.4

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Data collection

DiffractionMean temperature: 193 K / Serial crystal experiment: N
Diffraction sourceSource: LIQUID ANODE / Type: BRUKER METALJET / Wavelength: 1.54184 Å
DetectorType: Bruker PHOTON II / Detector: PIXEL / Date: Feb 1, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54184 Å / Relative weight: 1
ReflectionResolution: 1.71→55.74 Å / Num. obs: 18748 / % possible obs: 93 % / Redundancy: 3.9 % / CC1/2: 0.99 / Net I/σ(I): 11
Reflection shellResolution: 1.71→1.82 Å / Num. unique obs: 937 / CC1/2: 0.47

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
Aimlessdata scaling
DIMPLEphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.712→17.17 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.922 / SU R Cruickshank DPI: 0.165 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.141 / SU Rfree Blow DPI: 0.131 / SU Rfree Cruickshank DPI: 0.12
RfactorNum. reflection% reflectionSelection details
Rfree0.223 967 -RANDOM
Rwork0.1802 ---
obs0.1824 18718 85.5 %-
Displacement parametersBiso mean: 21.6 Å2
Baniso -1Baniso -2Baniso -3
1--0.0256 Å20 Å20 Å2
2--0.9443 Å20 Å2
3----0.9188 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.712→17.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1348 0 77 260 1685
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092831HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.985109HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d881SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes469HARMONIC5
X-RAY DIFFRACTIONt_it2831HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion189SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2839SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.68
X-RAY DIFFRACTIONt_other_torsion15.07
LS refinement shellResolution: 1.712→1.78 Å
RfactorNum. reflection% reflection
Rfree0.3671 27 -
Rwork0.287 --
obs--15.32 %
Refinement TLS params.Origin x: 17.2437 Å / Origin y: 6.6379 Å / Origin z: 14.4753 Å
111213212223313233
T-0.0251 Å20.0077 Å20.0083 Å2--0.0105 Å2-0.0033 Å2---0.045 Å2
L0.7137 °20.4313 °20.12 °2-1.0058 °20.128 °2--1.2682 °2
S-0.0154 Å °-0.0522 Å °-0.0091 Å °-0.0522 Å °-0.0657 Å °0.0366 Å °-0.0091 Å °0.0366 Å °0.0811 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A0 - 168
2X-RAY DIFFRACTION1{ A|* }A201 - 202

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