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- PDB-9qq1: KRAS-G12D(1-169) - GDP IN covalent COMPLEX with compound (3S,4R)-8 -

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Basic information

Entry
Database: PDB / ID: 9qq1
TitleKRAS-G12D(1-169) - GDP IN covalent COMPLEX with compound (3S,4R)-8
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE / K-RAS G12D / GTPASE / GDP BOUND / SWITCH 2 POCKET / COVALENT BINDING / SIGNALING PROTEIN / SMALL G- PROTEIN
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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells ...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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / skeletal muscle cell differentiation / 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 / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / positive regulation of glial cell proliferation / 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 / homeostasis of number of cells within a tissue / 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 / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / MAP2K and MAPK activation / Constitutive Signaling by EGFRvIII / 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 / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / 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 / negative regulation of neuron apoptotic process / gene expression / Ras protein signal transduction / mitochondrial outer membrane / 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: 1.3 Å
AuthorsOstermann, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Promise and Challenge of beta-Lactone Electrophiles to Target Aspartate 12 of Mutant KRAS G12D.
Authors: Budai, B. / Vaupel, A. / Dickson, C.J. / Beyer, K.S. / Guthy, D.A. / Ostermann, N. / McGregor, L.M. / De Kanter, R. / Weiss, A. / Linder, M. / Sager, E. / Bomio-Confaglia, C. / Proctor, R. / ...Authors: Budai, B. / Vaupel, A. / Dickson, C.J. / Beyer, K.S. / Guthy, D.A. / Ostermann, N. / McGregor, L.M. / De Kanter, R. / Weiss, A. / Linder, M. / Sager, E. / Bomio-Confaglia, C. / Proctor, R. / Leblanc, C. / Yuan, J. / Cotesta, S. / Wilcken, R. / Danilack, A.D. / Garcia, F. / Rogemoser, P. / Kazic-Legueux, M. / Zhang, Z. / Zheng, Q. / Shokat, K.M. / Brachmann, S.M. / Ehmke, V.
History
DepositionMar 31, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 23, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6454
Polymers19,3651
Non-polymers1,2803
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.242, 52.993, 89.772
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19364.730 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, small monomeric GTPase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-A1I9F / (2~{S})-4-[(1~{R},5~{S})-3-[7-(8-ethynyl-7-fluoranyl-3-oxidanyl-naphthalen-1-yl)-8-fluoranyl-2-[[(2~{R},8~{S})-2-fluoranyl-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-2-(oxan-4-ylmethyl)-4-oxidanylidene-butanoic acid


Mass: 812.876 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H47F3N6O6 / Feature type: SUBJECT OF INVESTIGATION
#4: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.47 Å3/Da / Density % sol: 50.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 30 % PEG 1000 0.2 M NaH2PO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.885604 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 9, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.885604 Å / Relative weight: 1
ReflectionResolution: 1.2→30.18 Å / Num. obs: 51569 / % possible obs: 92.7 % / Redundancy: 10.1 % / Rmerge(I) obs: 0.101 / Net I/σ(I): 10.1
Reflection shellResolution: 1.2→1.27 Å / Redundancy: 10.1 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2578 / Rpim(I) all: 0.7 / % possible all: 50.2

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Processing

Software
NameVersionClassificationNB
BUSTER2.11.8refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FGZF

Resolution: 1.3→24.01 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.957 / SU R Cruickshank DPI: 0.052 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.055 / SU Rfree Blow DPI: 0.053 / SU Rfree Cruickshank DPI: 0.051
RfactorNum. reflection% reflectionSelection details
Rfree0.2075 2359 -RANDOM
Rwork0.1967 ---
obs0.1972 46997 97.9 %-
Displacement parametersBiso mean: 23.23 Å2
Baniso -1Baniso -2Baniso -3
1-0.6227 Å20 Å20 Å2
2---0.5833 Å20 Å2
3----0.0394 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: LAST / Resolution: 1.3→24.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1305 0 88 211 1604
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0131457HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.261989HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d509SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes246HARMONIC5
X-RAY DIFFRACTIONt_it1457HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion192SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1614SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.3
X-RAY DIFFRACTIONt_other_torsion14.2
LS refinement shellResolution: 1.3→1.31 Å
RfactorNum. reflection% reflection
Rfree0.2602 45 -
Rwork0.2522 --
obs0.2526 940 79.23 %
Refinement TLS params.Origin x: -17.6567 Å / Origin y: -2.3912 Å / Origin z: 12.7362 Å
111213212223313233
T-0.0216 Å2-0.0121 Å20.0109 Å2--0.0324 Å2-0.0091 Å2---0.0289 Å2
L1.4971 °2-0.287 °2-0.5782 °2-1.236 °20.1738 °2--1.5077 °2
S-0.0053 Å °0.0311 Å °-0.0053 Å °0.0311 Å °0.0418 Å °0.0692 Å °-0.0053 Å °0.0692 Å °-0.0366 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 169
2X-RAY DIFFRACTION1{ A|* }A1001

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