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- PDB-7aca: CRYSTAL STRUCTURE OF AN ACTIVE KRAS G12D (GPPCP) DIMER IN COMPLEX... -

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Basic information

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


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / 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 / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / 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 / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / response to glucocorticoid / 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 / liver development / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / 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 / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
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 nucleotide triphosphate hydrolases ...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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / Chem-R6W / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.57 Å
AuthorsKessler, D.
CitationJournal: To Be Published
Title: CRYSTAL STRUCTURE OF AN ACTIVE KRAS G12D (GPPCP) DIMER IN COMPLEX WITH 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: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)81,12915
Polymers77,5474
Non-polymers3,58211
Water9,278515
1
A: GTPase KRas
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5347
Polymers38,7742
Non-polymers1,7605
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5968
Polymers38,7742
Non-polymers1,8226
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)69.264, 67.185, 71.435
Angle α, β, γ (deg.)90.00, 96.47, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 19386.848 Da / Num. of mol.: 4
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

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Non-polymers , 5 types, 526 molecules

#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*YM
#4: 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.: 2 / Source method: obtained synthetically / Formula: C40H40N6O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 515 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.16 Å3/Da / Density % sol: 43.15 %
Crystal growTemperature: 294 K / Method: vapor diffusion
Details: Morpheus Screen D12 Morpheus Alcohol 10% Morpheus Buffer 3 MPD_P1K_P3350 37.5% w/v

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999989 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999989 Å / Relative weight: 1
ReflectionResolution: 0.9999→68.82 Å / Num. obs: 88922 / % possible obs: 97.9 % / Redundancy: 3.5 % / Biso Wilson estimate: 21.67 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.052 / Rrim(I) all: 0.068 / Net I/σ(I): 11.6
Reflection shellResolution: 1.571→1.576 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 2 / Num. unique obs: 6403 / CC1/2: 0.8 / % possible all: 92.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QUU

6quu


Resolution: 1.57→22.99 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.949 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.092 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.095 / SU Rfree Blow DPI: 0.087 / SU Rfree Cruickshank DPI: 0.085
RfactorNum. reflection% reflectionSelection details
Rfree0.205 1858 2.09 %RANDOM
Rwork0.189 ---
obs0.189 88872 97.8 %-
Displacement parametersBiso mean: 28.63 Å2
Baniso -1Baniso -2Baniso -3
1--2.8954 Å20 Å23.7058 Å2
2---0.8115 Å20 Å2
3---3.7068 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.57→22.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5303 0 241 600 6144
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085642HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.977652HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2052SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes162HARMONIC2
X-RAY DIFFRACTIONt_gen_planes781HARMONIC5
X-RAY DIFFRACTIONt_it5642HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.33
X-RAY DIFFRACTIONt_other_torsion18.06
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion731SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7159SEMIHARMONIC4
LS refinement shellResolution: 1.57→1.61 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.217 153 2.39 %
Rwork0.22 6250 -
all0.22 6403 -
obs--95.46 %
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)
10.69620.00260.20070.8324-0.36991.0733-0.02180.06250.0218-0.018-0.00310.04860.0058-0.0520.0249-0.0193-0.001-0.0188-0.0442-0.0101-0.037118.1073-0.366557.8769
20.98030.31320.29250.78660.2811.23870.0123-0.09360.04860.0425-0.03440.02160.01720.01050.0221-0.0208-0.0007-0.0149-0.05530.0016-0.036353.85145.0793106.3527
32.3350.12191.35061.2624-0.47172.8036-0.0428-0.2947-0.04470.03240.11330.10330.0454-0.4689-0.0706-0.0961-0.0104-0.0045-0.02980.0174-0.103424.1423-6.640794.2308
42.62061.02691.54751.83341.24593.052-0.13920.3066-0.171-0.21150.2156-0.1532-0.10120.3598-0.0764-0.0905-0.00810.0148-0.0778-0.0175-0.118949.4509-3.578170.5367
50.19120.08690.183200.03770.03910.0412-0.0036-0.04840.00690.00550.00150.06960.0129-0.04670.03070.0074-0.0088-0.0257-0.0042-0.010836.9702-5.357482.2353
60.6796-0.01220.41480-0.19340.1191-0.03810.0197-0.0146-0.01260.03910.00720.0448-0.0151-0.0010.02780.0079-0.02770.0065-0.011-0.035236.5217-1.969782.2105
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ G|* }
6X-RAY DIFFRACTION6{ X|* }

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