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- PDB-5usj: Crystal Structure of human KRAS G12D mutant in complex with GDPNP -

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Basic information

Entry
Database: PDB / ID: 5usj
TitleCrystal Structure of human KRAS G12D mutant in complex with GDPNP
ComponentsGTPase KRas
KeywordsHYDROLASE / KRAS / GTPase
Function / homology
Function and homology information


endocrine signaling / forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / positive regulation of Rac protein signal transduction / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of glial cell proliferation ...endocrine signaling / forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / positive regulation of Rac protein signal transduction / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of glial cell proliferation / Signaling by RAS GTPase mutants / Signaling by RAS GAP mutants / Activation of RAS in B cells / RUNX3 regulates p14-ARF / RAS signaling downstream of NF1 loss-of-function variants / 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 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / homeostasis of number of cells within a tissue / Estrogen-stimulated signaling through PRKCZ / Signaling by PDGFRA extracellular domain mutants / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / SHC-mediated cascade:FGFR3 / Signaling by FGFR4 in disease / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR4 / Signaling by FLT3 ITD and TKD mutants / SHC-mediated cascade:FGFR1 / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Tie2 Signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / G protein activity / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / striated muscle cell differentiation / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in EGFR signaling / p38MAPK events / Signaling by FLT3 fusion proteins / FLT3 Signaling / EGFR Transactivation by Gastrin / small monomeric GTPase / GRB2 events in ERBB2 signaling / Signaling by FGFR1 in disease / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / NCAM signaling for neurite out-growth / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / visual learning / regulation of long-term neuronal synaptic plasticity / RAF activation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Ca2+ pathway / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / extrinsic component of cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / GDP binding / Negative regulation of MAPK pathway / regulation of protein stability / RAS processing / actin cytoskeleton organization / Signaling by RAF1 mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by moderate kinase activity BRAF mutants / Signaling by BRAF and RAF1 fusions / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ras protein signal transduction / neuron apoptotic process / RAF/MAP kinase cascade / mitochondrial outer membrane / negative regulation of neuron apoptotic process / GTPase activity / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Rho (Ras homology) subfamily of Ras-like small GTPases / Small GTPase / Ras family / Small GTP-binding protein domain / P-loop containing nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsHuang, C.S. / Kaplan, A. / Stockwell, B.R. / Tong, L.
CitationJournal: Cell / Year: 2017
Title: Multivalent Small-Molecule Pan-RAS Inhibitors.
Authors: Welsch, M.E. / Kaplan, A. / Chambers, J.M. / Stokes, M.E. / Bos, P.H. / Zask, A. / Zhang, Y. / Sanchez-Martin, M. / Badgley, M.A. / Huang, C.S. / Tran, T.H. / Akkiraju, H. / Brown, L.M. / ...Authors: Welsch, M.E. / Kaplan, A. / Chambers, J.M. / Stokes, M.E. / Bos, P.H. / Zask, A. / Zhang, Y. / Sanchez-Martin, M. / Badgley, M.A. / Huang, C.S. / Tran, T.H. / Akkiraju, H. / Brown, L.M. / Nandakumar, R. / Cremers, S. / Yang, W.S. / Tong, L. / Olive, K.P. / Ferrando, A. / Stockwell, B.R.
History
DepositionFeb 13, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support

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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
E: GTPase KRas
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,28618
Polymers129,0076
Non-polymers3,27912
Water12,827712
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0483
Polymers21,5011
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0483
Polymers21,5011
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0483
Polymers21,5011
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0483
Polymers21,5011
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0483
Polymers21,5011
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0483
Polymers21,5011
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.423, 63.491, 81.991
Angle α, β, γ (deg.)91.51, 112.63, 115.44
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 21501.164 Da / Num. of mol.: 6 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / References: UniProt: P01116
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / 5'-Guanylyl imidodiphosphate


Mass: 522.196 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 712 / Source method: isolated from a natural source / Formula: H2O

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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: 2.08 Å3/Da / Density % sol: 40.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 0.1 M Bis-Tris, 25% w/v PEG3350, pH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 14, 2013 / Details: MIRRORS
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 1.95→73.65 Å / Num. obs: 70797 / % possible obs: 92.5 % / Observed criterion σ(I): -3 / Redundancy: 1.9 % / Rmerge(I) obs: 0.058 / Net I/σ(I): 9.5
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.337 / Mean I/σ(I) obs: 2 / % possible all: 75.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.94→73.65 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.914 / SU B: 4.481 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.192 / ESU R Free: 0.177 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23848 3545 5 %RANDOM
Rwork0.1768 ---
obs0.17989 67215 92.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.808 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20.25 Å20.15 Å2
2---0.55 Å20.15 Å2
3---0.05 Å2
Refinement stepCycle: LAST / Resolution: 1.94→73.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8046 0 198 725 8969
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0198393
X-RAY DIFFRACTIONr_bond_other_d0.0010.027827
X-RAY DIFFRACTIONr_angle_refined_deg1.6561.98411370
X-RAY DIFFRACTIONr_angle_other_deg0.8318018
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.12251002
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.32324.303416
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.514151483
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0021562
X-RAY DIFFRACTIONr_chiral_restr0.0980.21263
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029374
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021908
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2092.1754032
X-RAY DIFFRACTIONr_mcbond_other2.2092.1754031
X-RAY DIFFRACTIONr_mcangle_it3.3093.2455026
X-RAY DIFFRACTIONr_mcangle_other3.3093.2455027
X-RAY DIFFRACTIONr_scbond_it3.2572.7054361
X-RAY DIFFRACTIONr_scbond_other3.2582.7054358
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.2383.8746342
X-RAY DIFFRACTIONr_long_range_B_refined7.57819.30410090
X-RAY DIFFRACTIONr_long_range_B_other7.54119.0359844
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.94→1.99 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 188 -
Rwork0.304 3657 -
obs--67.52 %

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