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- PDB-7tlg: Crystal Structure of small molecule beta-lactone 5 covalently bou... -

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Basic information

Entry
Database: PDB / ID: 7tlg
TitleCrystal Structure of small molecule beta-lactone 5 covalently bound to K-Ras(G12S)
ComponentsGTPase KRas
KeywordsONCOPROTEIN / Ras
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-I7H / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.80000720583 Å
AuthorsZiyang, Z. / Guiley, K.Z. / Shokat, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA244550 United States
CitationJournal: Nat.Chem.Biol. / Year: 2022
Title: Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).
Authors: Zhang, Z. / Guiley, K.Z. / Shokat, K.M.
History
DepositionJan 18, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 2.0Aug 10, 2022Group: Atomic model / Category: atom_site
Revision 2.1Nov 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7618
Polymers38,6732
Non-polymers2,0876
Water6,161342
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3804
Polymers19,3371
Non-polymers1,0443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3804
Polymers19,3371
Non-polymers1,0443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.550, 66.530, 60.800
Angle α, β, γ (deg.)90.000, 101.890, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLYGLYSERSER(chain A and (resseq 0:3 or (resid 4 and (name...AA0 - 651 - 66
12ARGARGASPASP(chain A and (resseq 0:3 or (resid 4 and (name...AA68 - 6969 - 70
13TYRTYRTHRTHR(chain A and (resseq 0:3 or (resid 4 and (name...AA71 - 8772 - 88
14SERSERLYSLYS(chain A and (resseq 0:3 or (resid 4 and (name...AA89 - 11790 - 118
15ASPASPTHRTHR(chain A and (resseq 0:3 or (resid 4 and (name...AA119 - 127120 - 128
16ALAALALEULEU(chain A and (resseq 0:3 or (resid 4 and (name...AA130 - 133131 - 134
17SERSERARGARG(chain A and (resseq 0:3 or (resid 4 and (name...AA136 - 149137 - 150
18GLYGLYLYSLYS(chain A and (resseq 0:3 or (resid 4 and (name...AA151 - 169152 - 170
19GDPGDPGDPGDP(chain A and (resseq 0:3 or (resid 4 and (name...AC201
210GLYGLYSERSER(chain B and (resseq 0:3 or (resid 4 and (name...BB0 - 651 - 66
211ARGARGASPASP(chain B and (resseq 0:3 or (resid 4 and (name...BB68 - 6969 - 70
212TYRTYRTHRTHR(chain B and (resseq 0:3 or (resid 4 and (name...BB71 - 8772 - 88
213SERSERLYSLYS(chain B and (resseq 0:3 or (resid 4 and (name...BB89 - 11790 - 118
214ASPASPTHRTHR(chain B and (resseq 0:3 or (resid 4 and (name...BB119 - 127120 - 128
215ALAALALEULEU(chain B and (resseq 0:3 or (resid 4 and (name...BB130 - 133131 - 134
216SERSERARGARG(chain B and (resseq 0:3 or (resid 4 and (name...BB136 - 149137 - 150
217GLYGLYLYSLYS(chain B and (resseq 0:3 or (resid 4 and (name...BB151 - 169152 - 170
218GDPGDPGDPGDP(chain B and (resseq 0:3 or (resid 4 and (name...BF201

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Components

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


Mass: 19336.721 Da / Num. of mol.: 2 / Mutation: G12S
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.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-I7H / (3R,4R)-1-[7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(4S,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3-hydroxypiperidine-4-carbaldehyde / (1R,6R)-3-[7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(4S,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-8-oxa-3-azabicyclo[4.2.0]octan-7-one


Mass: 576.061 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H31ClFN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 342 / 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: 2.13 Å3/Da / Density % sol: 42.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES, 30% PEG 4K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1.00002 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 23, 2021
RadiationMonochromator: Double-crystal Si(111) and multilayer / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 1.8→66.53 Å / Num. obs: 29901 / % possible obs: 99.4 % / Redundancy: 7 % / Biso Wilson estimate: 17.2960107706 Å2 / CC1/2: 0.997 / Net I/σ(I): 17
Reflection shellResolution: 1.8→1.84 Å / Num. unique obs: 1742 / CC1/2: 0.968

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOSFLMdata reduction
Aimlessdata scaling
PHENIXphasing
PHENIX1.10.1-2155refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6USZ

6usz


Resolution: 1.80000720583→44.3488584499 Å / SU ML: 0.217941797512 / Cross valid method: FREE R-VALUE / σ(F): 1.36458227077 / Phase error: 24.1559025054
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.233295099519 1464 4.90009037052 %
Rwork0.179014574786 28413 -
obs0.181667261326 29877 99.1932270916 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.2162748316 Å2
Refinement stepCycle: LAST / Resolution: 1.80000720583→44.3488584499 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2718 0 140 342 3200
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.02750788688732936
X-RAY DIFFRACTIONf_angle_d1.20834382293971
X-RAY DIFFRACTIONf_chiral_restr0.0629633595213433
X-RAY DIFFRACTIONf_plane_restr0.00691887499335496
X-RAY DIFFRACTIONf_dihedral_angle_d13.98003316941737
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.80000720583-1.86430.333915243371460.2318643917342783X-RAY DIFFRACTION98.5863345675
1.8643-1.9390.3135219438191370.2169880490612803X-RAY DIFFRACTION98.459477562
1.939-2.02720.2886869780411420.202771830462828X-RAY DIFFRACTION98.8352745424
2.0272-2.13410.2841478467841560.1998320343552820X-RAY DIFFRACTION98.9361702128
2.1341-2.26780.264818161541390.1916870821212846X-RAY DIFFRACTION99.1035856574
2.2678-2.44290.2531024321521720.1907579743872826X-RAY DIFFRACTION99.2058239576
2.4429-2.68870.2463961558581310.1953327216792837X-RAY DIFFRACTION99.6307485733
2.6887-3.07770.2597757189221520.1831786586982860X-RAY DIFFRACTION99.6690933157
3.0777-3.87720.1924283260811400.1558454117722886X-RAY DIFFRACTION99.7692054072
3.8772-4.436230.1647825580381490.1503698932462924X-RAY DIFFRACTION99.70798183

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