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- PDB-5oco: Discovery of small molecules binding to KRAS via high affinity an... -

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Entry
Database: PDB / ID: 5oco
TitleDiscovery of small molecules binding to KRAS via high affinity antibody fragment competition method.
ComponentsGTPase KRas
KeywordsHYDROLASE / Domain antibodies / small molecules / drug fragment screening
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / 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 / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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 CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
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 nucleotide triphosphate hydrolases ...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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-9RK / CITRIC ACID / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / DI(HYDROXYETHYL)ETHER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsCruz-Migoni, A. / Ehebauer, M.T. / Phillips, S.E.V. / Quevedo, C.E. / Rabbitts, T.H.
CitationJournal: Nat Commun / Year: 2018
Title: Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment.
Authors: Quevedo, C.E. / Cruz-Migoni, A. / Bery, N. / Miller, A. / Tanaka, T. / Petch, D. / Bataille, C.J.R. / Lee, L.Y.W. / Fallon, P.S. / Tulmin, H. / Ehebauer, M.T. / Fernandez-Fuentes, N. / ...Authors: Quevedo, C.E. / Cruz-Migoni, A. / Bery, N. / Miller, A. / Tanaka, T. / Petch, D. / Bataille, C.J.R. / Lee, L.Y.W. / Fallon, P.S. / Tulmin, H. / Ehebauer, M.T. / Fernandez-Fuentes, N. / Russell, A.J. / Carr, S.B. / Phillips, S.E.V. / Rabbitts, T.H.
History
DepositionJul 3, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 22, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.2Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.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
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: GTPase KRas
A: GTPase KRas
C: GTPase KRas
D: GTPase KRas
E: GTPase KRas
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,24727
Polymers128,9896
Non-polymers5,25821
Water9,980554
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16160 Å2
ΔGint-85 kcal/mol
Surface area42600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.600, 118.760, 156.900
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21A
12B
22C
13B
23D
14B
24E
15B
25F
16A
26C
17A
27D
18A
28E
19A
29F
110C
210D
111C
211E
112C
212F
113D
213E
114D
214F
115E
215F

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: TYR / Beg label comp-ID: TYR / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSBA-3 - 16715 - 185
21LYSLYSAB-3 - 16715 - 185
12LYSLYSBA-3 - 16715 - 185
22LYSLYSCC-3 - 16715 - 185
13LYSLYSBA-3 - 16715 - 185
23LYSLYSDD-3 - 16715 - 185
14LYSLYSBA-3 - 16915 - 187
24LYSLYSEE-3 - 16915 - 187
15LYSLYSBA-3 - 16715 - 185
25LYSLYSFF-3 - 16715 - 185
16GLUGLUAB-3 - 16815 - 186
26GLUGLUCC-3 - 16815 - 186
17GLUGLUAB-3 - 16815 - 186
27GLUGLUDD-3 - 16815 - 186
18LYSLYSAB-3 - 16715 - 185
28LYSLYSEE-3 - 16715 - 185
19GLUGLUAB-3 - 16815 - 186
29GLUGLUFF-3 - 16815 - 186
110GLUGLUCC-3 - 16815 - 186
210GLUGLUDD-3 - 16815 - 186
111LYSLYSCC-3 - 16715 - 185
211LYSLYSEE-3 - 16715 - 185
112GLUGLUCC-3 - 16815 - 186
212GLUGLUFF-3 - 16815 - 186
113LYSLYSDD-3 - 16715 - 185
213LYSLYSEE-3 - 16715 - 185
114GLUGLUDD-3 - 16815 - 186
214GLUGLUFF-3 - 16815 - 186
115LYSLYSEE-3 - 16715 - 185
215LYSLYSFF-3 - 16715 - 185

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

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Components

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Protein , 1 types, 6 molecules BACDEF

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


Mass: 21498.164 Da / Num. of mol.: 6 / Mutation: Q61H
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

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Non-polymers , 6 types, 575 molecules

#2: Chemical
ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#3: Chemical
ChemComp-9RK / ~{N}-[[(3~{R})-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]furan-2-carboxamide


Mass: 259.257 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C14H13NO4
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H8O7
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 554 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 2.52 Å3/Da / Density % sol: 51.14 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 8-15% w/v Polyethylene Glycol 3350 and 0.2 M lithium citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 31, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.66→59.38 Å / Num. obs: 140853 / % possible obs: 100 % / Redundancy: 13.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.032 / Net I/σ(I): 13.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data reduction
xia2data scaling
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GFT

3gft


Resolution: 1.66→59.38 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.281 / SU ML: 0.073 / Cross valid method: THROUGHOUT / ESU R: 0.093 / ESU R Free: 0.091 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20544 7000 5 %RANDOM
Rwork0.17855 ---
obs0.17989 133751 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 35.755 Å2
Baniso -1Baniso -2Baniso -3
1--0.78 Å20 Å20 Å2
2--1.09 Å20 Å2
3----0.31 Å2
Refinement stepCycle: 1 / Resolution: 1.66→59.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8221 0 339 554 9114
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0198844
X-RAY DIFFRACTIONr_bond_other_d0.0020.027968
X-RAY DIFFRACTIONr_angle_refined_deg2.1371.98612000
X-RAY DIFFRACTIONr_angle_other_deg1.095318508
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.60251062
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.99724.501431
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.786151528
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5851560
X-RAY DIFFRACTIONr_chiral_restr0.1280.21311
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0210164
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021804
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_it3.9623.2374197
X-RAY DIFFRACTIONr_mcbond_other3.9583.2364196
X-RAY DIFFRACTIONr_mcangle_it5.4394.8215258
X-RAY DIFFRACTIONr_mcangle_other5.4394.8225259
X-RAY DIFFRACTIONr_scbond_it5.5733.9924647
X-RAY DIFFRACTIONr_scbond_other5.5723.9934648
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.3125.7146737
X-RAY DIFFRACTIONr_long_range_B_refined10.18339.2459744
X-RAY DIFFRACTIONr_long_range_B_other10.18539.2569745
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11B107220.1
12A107220.1
21B109820.06
22C109820.06
31B109940.07
32D109940.07
41B110920.08
42E110920.08
51B109780.07
52F109780.07
61A108720.1
62C108720.1
71A109220.1
72D109220.1
81A107580.1
82E107580.1
91A108360.09
92F108360.09
101C110940.07
102D110940.07
111C111520.06
112E111520.06
121C112040.07
122F112040.07
131D110980.08
132E110980.08
141D111800.07
142F111800.07
151E111580.07
152F111580.07
LS refinement shellResolution: 1.66→1.703 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 514 -
Rwork0.304 9763 -
obs--100 %

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