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- PDB-7acq: CRYSTAL STRUCTURE OF INACTIVE KRAS G12D (GDP) IN COMPLEX WITH THE... -

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Basic information

Entry
Database: PDB / ID: 7acq
TitleCRYSTAL STRUCTURE OF INACTIVE KRAS G12D (GDP) 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
GUANOSINE-5'-DIPHOSPHATE / Chem-R6W / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsKessler, D.
CitationJournal: To Be Published
Title: CRYSTAL STRUCTURE OF INACTIVE KRAS G12D (GDP) IN COMPLEX WITH THE SOAKED DIMERIC INHIBITOR BI00925747
Authors: Kessler, D.
History
DepositionSep 11, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,90111
Polymers58,1613
Non-polymers2,7408
Water8,737485
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)114.883, 66.316, 74.537
Angle α, β, γ (deg.)90.00, 95.12, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-313-

HOH

21C-370-

HOH

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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.: 3
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-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: Mg
#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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 485 / 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: 2.38 Å3/Da / Density % sol: 48.38 %
Crystal growTemperature: 278 K / Method: vapor diffusion / Details: 200 mM CaCl2 100 mM MES pH6 PEG6000 20% W/v

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.857→74 Å / Num. obs: 43278 / % possible obs: 91.6 % / Redundancy: 3.5 % / CC1/2: 1 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.052 / Rrim(I) all: 0.098 / Net I/σ(I): 10.5
Reflection shellResolution: 1.858→1.863 Å / Num. unique obs: 2192 / CC1/2: 0.8

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QUU
Resolution: 1.86→37.12 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 21.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2097 2192 5.1 %
Rwork0.1737 --
obs0.1755 43017 91.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.86→37.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3864 0 187 485 4536
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084125
X-RAY DIFFRACTIONf_angle_d1.1285592
X-RAY DIFFRACTIONf_dihedral_angle_d15.5272528
X-RAY DIFFRACTIONf_chiral_restr0.321621
X-RAY DIFFRACTIONf_plane_restr0.006694
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.90040.30291600.25072750X-RAY DIFFRACTION100
1.9004-1.94470.24971070.21591862X-RAY DIFFRACTION67
1.9447-1.99330.21731350.19732747X-RAY DIFFRACTION99
1.9933-2.04720.24041500.1942537X-RAY DIFFRACTION97
2.0472-2.10740.2445400.2089540X-RAY DIFFRACTION86
2.1074-2.17540.22551280.19372785X-RAY DIFFRACTION99
2.1754-2.25320.25221400.17962708X-RAY DIFFRACTION97
2.2532-2.34340.21271580.17952686X-RAY DIFFRACTION97
2.3434-2.450.22081860.17272725X-RAY DIFFRACTION99
2.45-2.57910.20421580.17382755X-RAY DIFFRACTION99
2.5791-2.74070.2271340.17662796X-RAY DIFFRACTION100
2.7407-2.95220.20551440.17732753X-RAY DIFFRACTION99
2.9522-3.24910.21231500.17252736X-RAY DIFFRACTION98
3.2491-3.71890.19941460.15852776X-RAY DIFFRACTION99
3.7189-4.6840.16561290.13832826X-RAY DIFFRACTION100
4.684-100.19431270.18412843X-RAY DIFFRACTION98
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.2131-0.16920.12650.41070.28692.52180.04070.0186-0.2564-0.0213-0.06150.00840.2457-0.10230.0170.1454-0.0108-0.01540.1348-0.01060.188927.59615.270349.0613
24.70561.1068-0.20714.2503-1.78680.89520.0427-0.2669-1.24240.1514-0.3623-0.83250.3240.45740.120.24060.0140.01030.26370.01290.426642.5906-0.148149.7622
31.7153-0.0203-1.36730.32260.34932.9495-0.1176-0.3317-0.11160.0663-0.1064-0.2210.18020.57150.03890.1160.0056-0.02710.21830.05840.191640.9138.306959.9164
42.0657-0.1105-0.62331.6554-0.32442.70110.0906-0.09040.02810.3608-0.066-0.1169-0.3245-0.0924-0.06060.1246-0.0042-0.05770.1147-0.01420.174135.249212.555860.9465
54.10430.58180.06981.8782-0.20022.59160.1603-0.45210.16350.3521-0.1259-0.0866-0.21210.06130.01580.1915-0.0292-0.030.1985-0.01420.151332.505216.89962.064
66.63091.7743-1.1223.5833-1.49633.76680.11790.10790.22490.0233-0.1086-0.1435-0.22950.10790.020.12620.0048-0.02170.10130.0240.143732.171217.424547.8231
71.36330.60530.50181.6321-0.03132.239-0.03010.04180.0961-0.0270.02150.105-0.0184-0.1850.01240.0986-0.00230.01080.1247-0.00360.151933.567-1.054723.5169
80.29740.5242-0.20844.83870.8490.4537-0.0921-0.23010.5604-0.52110.07780.8872-0.4303-0.64370.04120.31780.0416-0.0410.40730.05480.47523.8708-1.209818.2911
91.9894-0.72430.11544.1327-0.85632.68250.0502-0.0829-0.01910.058-0.05620.05820.1575-0.1594-0.01150.1565-0.01720.01090.1345-0.0080.170835.2642-4.561231.041
104.68051.49182.4095.25140.94322.185-0.40530.06941.2771-0.5619-0.02550.7941-0.9096-0.41930.17520.30070.0391-0.04120.2602-0.03990.421134.991213.661524.9066
110.87120.48140.75231.56841.22133.453-0.13320.12590.1127-0.2340.021-0.1239-0.41510.1520.06090.1753-0.0335-0.02360.11950.02610.167941.35337.622814.247
121.68281.24211.163.54172.37453.5615-0.02930.160.127-0.00550.1101-0.3333-0.08030.32350.00130.1463-0.01890.00550.11840.04670.226446.1995.494121.1461
130.58771.201-0.16052.7813-0.25851.9326-0.34910.3836-0.4489-0.58370.3987-0.15790.7930.11880.03650.4045-0.0527-0.02850.27160.00770.224237.4335-5.59513.5488
144.05613.25832.53837.5064.46798.11820.25930.5788-0.0672-0.4204-0.0334-0.7594-0.15620.6097-0.05080.2330.0120.08230.32550.01520.245850.66530.43549.3944
154.50572.4240.39923.37740.15761.6735-0.33960.3586-0.2568-0.50370.309-0.15860.06870.1244-0.00290.1835-0.01770.00990.1831-0.01130.144339.5101-7.57714.6073
165.65172.05941.56714.26260.07653.55370.1361-0.0766-0.01220.1382-0.1058-0.2010.07220.19470.0120.10820.00860.00630.12150.00570.165644.8597-4.450926.4473
172.0699-0.8813-0.54123.2758-0.26612.72560.00250.07630.0642-0.196-0.0482-0.2299-0.01330.07670.06160.1134-0.0081-0.02420.12790.0040.188850.110541.579123.4981
184.5522-3.08811.1313.1927-0.31590.42240.3670.2660.3666-0.1917-0.4221-1.1468-0.00160.74360.10170.34380.00440.08470.44130.05060.548954.816950.051218.2864
194.2262-1.3182-0.75383.05150.13782.7658-0.0618-0.09850.10570.11070.0356-0.0561-0.2811-0.0404-0.00020.1360.016-0.0390.1483-0.01650.210646.219441.828131.0078
206.3148-1.6090.61227.7796-1.97151.80370.09790.1783-0.2862-0.1951-0.1577-1.60070.51480.7530.17850.20840.036-0.05270.2993-0.03760.497761.485532.535125.4228
211.7288-1.05750.98382.779-1.26262.84920.28930.4783-0.3053-0.5911-0.4505-0.31920.21460.43020.04150.27710.11330.0730.2406-0.0410.217553.855330.548714.1965
222.1962-0.69410.06492.8762-0.53861.99730.19330.4535-0.2537-0.6971-0.03990.20360.1943-0.1556-0.06680.27230.0389-0.01040.2267-0.05430.207947.266533.27913.1637
233.8388-1.81520.92024.4283-1.56083.48-0.23170.7636-0.6011-1.00050.22340.4850.29120.0036-0.17430.6313-0.0057-0.19190.2783-0.26970.370143.0826.0019.1783
242.226-1.21830.36417.6612-0.52921.28540.22610.2372-0.0725-1.0179-0.20710.34370.0858-0.0525-0.03180.27890.0396-0.04330.16-0.00090.173641.569539.685714.4906
253.4078-0.9701-0.57179.0364-2.00513.349-0.07450.0173-0.4860.2030.16140.16780.1-0.2525-0.05710.0979-0.0095-0.02070.1154-0.00940.205241.528433.4526.3355
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 57 )
2X-RAY DIFFRACTION2chain 'A' and (resid 58 through 74 )
3X-RAY DIFFRACTION3chain 'A' and (resid 75 through 103 )
4X-RAY DIFFRACTION4chain 'A' and (resid 104 through 126 )
5X-RAY DIFFRACTION5chain 'A' and (resid 127 through 151 )
6X-RAY DIFFRACTION6chain 'A' and (resid 152 through 167 )
7X-RAY DIFFRACTION7chain 'B' and (resid 1 through 25 )
8X-RAY DIFFRACTION8chain 'B' and (resid 26 through 37 )
9X-RAY DIFFRACTION9chain 'B' and (resid 38 through 57 )
10X-RAY DIFFRACTION10chain 'B' and (resid 58 through 74 )
11X-RAY DIFFRACTION11chain 'B' and (resid 75 through 103 )
12X-RAY DIFFRACTION12chain 'B' and (resid 104 through 116 )
13X-RAY DIFFRACTION13chain 'B' and (resid 117 through 126 )
14X-RAY DIFFRACTION14chain 'B' and (resid 127 through 137 )
15X-RAY DIFFRACTION15chain 'B' and (resid 138 through 151 )
16X-RAY DIFFRACTION16chain 'B' and (resid 152 through 167 )
17X-RAY DIFFRACTION17chain 'C' and (resid 1 through 25 )
18X-RAY DIFFRACTION18chain 'C' and (resid 26 through 37 )
19X-RAY DIFFRACTION19chain 'C' and (resid 38 through 57 )
20X-RAY DIFFRACTION20chain 'C' and (resid 58 through 74 )
21X-RAY DIFFRACTION21chain 'C' and (resid 75 through 103 )
22X-RAY DIFFRACTION22chain 'C' and (resid 104 through 126 )
23X-RAY DIFFRACTION23chain 'C' and (resid 127 through 137 )
24X-RAY DIFFRACTION24chain 'C' and (resid 138 through 151 )
25X-RAY DIFFRACTION25chain 'C' and (resid 152 through 167 )

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