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- PDB-6wgn: Crystal structure of K-Ras(G12D) GppNHp bound to cyclic peptide l... -

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Basic information

Entry
Database: PDB / ID: 6wgn
TitleCrystal structure of K-Ras(G12D) GppNHp bound to cyclic peptide ligand KD2
Components
  • Cyclic Peptide KD2
  • GTPase KRas
KeywordsSIGNALING PROTEIN/INHIBITOR / Inhibitor / K-Ras / Selective / Cyclic Peptide / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


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 / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / 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 / GDP binding / 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 / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / Ras protein signal transduction / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.601 Å
AuthorsZhang, Z. / Gao, R. / Hu, Q. / Peacock, H. / Peacock, D.M. / Shokat, K.M. / Suga, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA244550 United States
CitationJournal: Acs Cent.Sci. / Year: 2020
Title: GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf.
Authors: Zhang, Z. / Gao, R. / Hu, Q. / Peacock, H. / Peacock, D.M. / Dai, S. / Shokat, K.M. / Suga, H.
History
DepositionApr 6, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 18, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 18, 2023Group: 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
E: Cyclic Peptide KD2
F: Cyclic Peptide KD2
G: Cyclic Peptide KD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,22412
Polymers63,5846
Non-polymers1,6406
Water10,341574
1
A: GTPase KRas
F: Cyclic Peptide KD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,7414
Polymers21,1952
Non-polymers5472
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2320 Å2
ΔGint-21 kcal/mol
Surface area8910 Å2
MethodPISA
2
B: GTPase KRas
G: Cyclic Peptide KD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,7414
Polymers21,1952
Non-polymers5472
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-22 kcal/mol
Surface area8910 Å2
MethodPISA
3
C: GTPase KRas
E: Cyclic Peptide KD2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,7414
Polymers21,1952
Non-polymers5472
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2030 Å2
ΔGint-20 kcal/mol
Surface area8910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.437, 79.155, 90.982
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19307.680 Da / Num. of mol.: 3 / Mutation: G12D, C51S, C80L, C118S
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
#2: Protein/peptide Cyclic Peptide KD2


Mass: 1887.152 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / 5'-Guanylyl imidodiphosphate


Mass: 522.196 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 574 / 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: 2.05 Å3/Da / Density % sol: 40.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 9 / Details: PEG 4000, Tris, Lithium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 14, 2018
RadiationMonochromator: KOHZU / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 69379 / % possible obs: 99.9 % / Redundancy: 9.6 % / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.037 / Rrim(I) all: 0.116 / Χ2: 0.763 / Net I/σ(I): 5.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.6-1.637.70.7534180.8620.2860.8040.152100
1.63-1.668.20.63934130.9040.2350.6810.157100
1.66-1.698.60.60534500.9270.2160.6430.168100
1.69-1.729.30.67134260.9050.2290.710.448100
1.72-1.76100.42534310.9630.140.4480.197100
1.76-1.8100.33934200.9690.1120.3570.23100
1.8-1.85100.29434530.9780.0960.3090.273100
1.85-1.9100.63334280.9540.2050.6651.326100
1.9-1.959.90.49434390.9160.1650.5211.892100
1.95-2.02100.18234430.9860.060.1920.523100
2.02-2.099.80.36334440.9440.1220.3831.869100
2.09-2.1710.10.12334460.990.040.1290.504100
2.17-2.279.90.23534770.9340.080.2481.617100
2.27-2.3910.10.10134600.9920.0330.1070.634100
2.39-2.5410.10.09434760.9930.030.0990.673100
2.54-2.74100.11434840.9910.0370.121.171100
2.74-3.01100.08935050.9930.0290.0940.943100
3.01-3.459.90.08835420.9930.0290.0931.107100
3.45-4.349.70.06135470.9960.020.0650.825100
4.34-509.50.03236770.9980.0110.0340.19498.4

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.14-3260refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5USJ

5usj


Resolution: 1.601→38.524 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 20.66
RfactorNum. reflection% reflection
Rfree0.2139 3261 4.91 %
Rwork0.1839 --
obs0.1854 66445 95.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 67.86 Å2 / Biso mean: 19.6076 Å2 / Biso min: 5.17 Å2
Refinement stepCycle: final / Resolution: 1.601→38.524 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4334 0 99 574 5007
Biso mean--12.72 29.47 -
Num. residues----536
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6013-1.62520.2377750.1968166458
1.6252-1.65060.2221050.197217176
1.6506-1.67760.24951530.1955245188
1.6776-1.70660.22661390.2013254991
1.7066-1.73760.24641320.1867271495
1.7376-1.7710.20381380.177280199
1.771-1.80720.241520.1756283099
1.8072-1.84650.22271500.192837100
1.8465-1.88940.28021170.2249284599
1.8894-1.93670.31961310.2804279098
1.9367-1.9890.2251490.18232854100
1.989-2.04760.21031290.18792856100
2.0476-2.11360.26261620.20782839100
2.1136-2.18920.19761490.16622862100
2.1892-2.27680.25231500.2043282899
2.2768-2.38040.21631700.17172844100
2.3804-2.50590.20411460.1762872100
2.5059-2.66290.20541550.17632869100
2.6629-2.86840.18471360.18262908100
2.8684-3.1570.23361550.18032915100
3.157-3.61350.18181400.16842923100
3.6135-4.55140.1731560.15092946100
4.5514-38.5240.20211720.1948301698

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