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- PDB-7ewa: GDP-bound KRAS G12D in complex with TH-Z827 -

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Basic information

Entry
Database: PDB / ID: 7ewa
TitleGDP-bound KRAS G12D in complex with TH-Z827
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE / KRAS / G12D / Salt-bridge / Inhibitor / Complex / TH-Z827
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / SHC-mediated cascade:FGFR2 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / Signaling by CSF1 (M-CSF) in myeloid cells / Regulation of RAS by GAPs / 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 / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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
Chem-05F / GUANOSINE-5'-DIPHOSPHATE / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsShen, P. / Yang, Y. / Yang, Y. / Zhang, L. / Chen, C.-C. / Guo, R.-T.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81991492 China
CitationJournal: Cell Discov / Year: 2022
Title: KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge.
Authors: Mao, Z. / Xiao, H. / Shen, P. / Yang, Y. / Xue, J. / Yang, Y. / Shang, Y. / Zhang, L. / Li, X. / Zhang, Y. / Du, Y. / Chen, C.C. / Guo, R.T. / Zhang, Y.
History
DepositionMay 25, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 29, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
B: Isoform 2B of GTPase KRas
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,71811
Polymers58,1613
Non-polymers2,5588
Water3,045169
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3534
Polymers19,3871
Non-polymers9663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-19 kcal/mol
Surface area7910 Å2
MethodPISA
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4324
Polymers19,3871
Non-polymers1,0453
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint-14 kcal/mol
Surface area7760 Å2
MethodPISA
3
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9333
Polymers19,3871
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint-13 kcal/mol
Surface area7580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.691, 102.793, 56.395
Angle α, β, γ (deg.)90.000, 107.100, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 3 molecules ABC

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


Mass: 19386.848 Da / Num. of mol.: 3 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, small monomeric GTPase

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Non-polymers , 5 types, 177 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-05F / 4-[(1~{R},5~{S})-3,8-diazabicyclo[3.2.1]octan-8-yl]-7-(8-methylnaphthalen-1-yl)-2-[[(2~{S})-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5~{H}-pyrido[3,4-d]pyrimidine


Mass: 498.662 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H38N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.2 Å3/Da / Density % sol: 44.17 %
Crystal growTemperature: 297 K / Method: evaporation / pH: 8.5
Details: 0.2 M sodium acetate, 0.1 M Tris, pH 8.5, 26 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: LIQUID ANODE / Type: BRUKER METALJET / Wavelength: 1.34138 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: May 2, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.34138 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 47529 / % possible obs: 100 % / Redundancy: 9.07 % / CC1/2: 1 / Rmerge(I) obs: 0.0844 / Net I/σ(I): 12.63
Reflection shellResolution: 2.25→2.28 Å / Redundancy: 6.72 % / Rmerge(I) obs: 0.3976 / Mean I/σ(I) obs: 3.33 / Num. unique obs: 946 / CC1/2: 0.95 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
SADABSdata scaling
PDB_EXTRACT3.27data extraction
SAINTdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EPR

4epr


Resolution: 2.25→33.7 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 30.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2584 3944 8.3 %
Rwork0.203 43585 -
obs0.2076 47529 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 100.64 Å2 / Biso mean: 43.4692 Å2 / Biso min: 19.31 Å2
Refinement stepCycle: final / Resolution: 2.25→33.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3902 0 169 169 4240
Biso mean--40.37 43.52 -
Num. residues----490
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 28

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.25-2.280.30391440.277115661710100
2.28-2.310.32991420.269215711713100
2.31-2.340.33641390.270115561695100
2.34-2.370.28461400.251215481688100
2.37-2.40.3011410.259215561697100
2.4-2.440.3581400.257215611701100
2.44-2.480.33281420.271815631705100
2.48-2.520.35161370.263115031640100
2.52-2.560.30281410.237115921733100
2.56-2.610.30031400.222615691709100
2.61-2.660.27071390.218115271666100
2.66-2.710.33951430.238215781721100
2.71-2.770.32651400.244415551695100
2.77-2.830.34751410.235715381679100
2.83-2.910.33251390.232415771716100
2.91-2.980.32821390.224715521691100
2.98-3.070.28531410.237415881729100
3.07-3.170.25791380.214815231661100
3.17-3.280.28921430.209315601703100
3.28-3.420.26821430.194315531696100
3.42-3.570.25891420.188915901732100
3.57-3.760.26411390.185415611700100
3.76-3.990.23341360.17815261662100
3.99-4.30.18531440.159315591703100
4.3-4.730.20761430.156815751718100
4.73-5.410.20681390.157715301669100
5.42-6.810.22491440.213315691713100
6.82-33.70.21161450.18641539168499

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