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- PDB-7ach: CRYSTAL STRUCTURE OF ACTIVE KRAS G12D (GPPCP) IN COMPLEX WITH THE... -

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Basic information

Entry
Database: PDB / ID: 7ach
TitleCRYSTAL STRUCTURE OF ACTIVE KRAS G12D (GPPCP) IN COMPLEX WITH THE SOAKED DIMERIC INHIBITOR BI-5747
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / VIENNA / PPI
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / 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 / glial cell proliferation / 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 / 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:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / Signaling by RAF1 mutants / GDP binding / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
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
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / Chem-R6W / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsKessler, D.
CitationJournal: To Be Published
Title: CRYSTAL STRUCTURE OF ACTIVE KRAS G12D (GPPCP) IN COMPLEX WITH THE SOAKED DIMERIC INHIBITOR BI-5747
Authors: Kessler, D.
History
DepositionSep 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5347
Polymers38,7742
Non-polymers1,7605
Water3,207178
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3800 Å2
ΔGint-30 kcal/mol
Surface area14530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.018, 72.773, 54.437
Angle α, β, γ (deg.)90.00, 103.57, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 19386.848 Da / Num. of mol.: 2
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-R6W / (3~{S})-5-oxidanyl-3-[2-[[6-[[3-[(1~{S})-6-oxidanyl-3-oxidanylidene-1,2-dihydroisoindol-1-yl]-1~{H}-indol-2-yl]methylamino]hexylamino]methyl]-1~{H}-indol-3-yl]-2,3-dihydroisoindol-1-one


Mass: 668.783 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H40N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 178 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.14 Å3/Da / Density % sol: 42.42 %
Crystal growTemperature: 278 K / Method: vapor diffusion / Details: MPD 51% v/v 50mM MES pH 6.4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: RIGAKU / Detector: CCD / Date: Feb 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.9→36.26 Å / Num. obs: 17502 / % possible obs: 74.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 21.32 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.036 / Rrim(I) all: 0.067 / Net I/σ(I): 18.8
Reflection shellResolution: 1.905→1.911 Å / Redundancy: 1.2 % / Mean I/σ(I) obs: 2.3 / Num. unique obs: 456 / CC1/2: 1 / % possible all: 20

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION March 1data reduction
autoPROC(Version 1.1.6)data scaling
Aimlessdata scaling
BUSTER2.11.6refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QUU

6quu


Resolution: 1.9→36.26 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.92 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.271 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.281 / SU Rfree Blow DPI: 0.19 / SU Rfree Cruickshank DPI: 0.19
RfactorNum. reflection% reflectionSelection details
Rfree0.214 876 5.01 %RANDOM
Rwork0.173 ---
obs0.175 17490 67.8 %-
Displacement parametersBiso mean: 26.31 Å2
Baniso -1Baniso -2Baniso -3
1--1.139 Å20 Å22.0438 Å2
2--1.9014 Å20 Å2
3----0.7624 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.9→36.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2661 0 116 178 2955
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082846HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.993863HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1036SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes82HARMONIC2
X-RAY DIFFRACTIONt_gen_planes396HARMONIC5
X-RAY DIFFRACTIONt_it2846HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion19.76
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion369SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3314SEMIHARMONIC4
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.217 -7.02 %
Rwork-424 -
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.72931.10840.57722.59340.11641.50990.0564-0.0195-0.04340.14020.0208-0.0494-0.0292-0.0402-0.0772-0.06560-0.0124-0.0773-0.0042-0.065113.5322-14.176938.731
21.206-0.20040.02671.90150.52811.8390.00880.00190.0192-0.1326-0.02740.0487-0.09670.00830.0186-0.06980.0144-0.0248-0.0611-0.0063-0.0471-2.585-21.730913.1401
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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