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- PDB-6f76: Antibody derived (Abd-8) small molecule binding to KRAS. -

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Basic information

Entry
Database: PDB / ID: 6f76
TitleAntibody derived (Abd-8) small molecule binding to KRAS.
ComponentsGTPase KRas
KeywordsONCOPROTEIN / Abd-8 / inhibitor / KRAS
Function / homology
Function and homology information


GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis ...GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / 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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / 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 / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / positive regulation of glial cell proliferation / 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 / homeostasis of number of cells within a tissue / 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 / response to glucocorticoid / 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 / female pregnancy / RAF activation / liver development / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / cytokine-mediated signaling 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of cellular senescence / MAPK cascade / DAP12 signaling
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 domain 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-CVK / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsBery, N. / Cruz-Migoni, A. / Quevedo, C.E. / Phillips, S.V.E. / Carr, S. / Rabbitts, T.H.
Funding support United Kingdom, 4items
OrganizationGrant numberCountry
Wellcome Trust100842/z/12/z United Kingdom
Wellcome Trust099246/z/12/z United Kingdom
Bloodwise12051 United Kingdom
Medical Research Council (United Kingdom)MR/J000612/1 United Kingdom
CitationJournal: Elife / Year: 2018
Title: BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions.
Authors: Bery, N. / Cruz-Migoni, A. / Bataille, C.J. / Quevedo, C.E. / Tulmin, H. / Miller, A. / Russell, A. / Phillips, S.E. / Carr, S.B. / Rabbitts, T.H.
History
DepositionDec 7, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1May 8, 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_struct_conn_angle / struct_conn / 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_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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
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)122,95222
Polymers118,1116
Non-polymers4,84116
Water1,04558
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15470 Å2
ΔGint-87 kcal/mol
Surface area41280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.190, 118.424, 156.751
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: ALA / Beg label comp-ID: ALA / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUBA-3 - 1681 - 172
21GLUGLUAB-3 - 1681 - 172
12GLUGLUBA-3 - 1681 - 172
22GLUGLUCC-3 - 1681 - 172
13LYSLYSBA-3 - 1671 - 171
23LYSLYSDD-3 - 1671 - 171
14GLUGLUBA-3 - 1681 - 172
24GLUGLUEE-3 - 1681 - 172
15GLUGLUBA-3 - 1681 - 172
25GLUGLUFF-3 - 1681 - 172
16GLUGLUAB-3 - 1681 - 172
26GLUGLUCC-3 - 1681 - 172
17LYSLYSAB-3 - 1671 - 171
27LYSLYSDD-3 - 1671 - 171
18GLUGLUAB-3 - 1681 - 172
28GLUGLUEE-3 - 1681 - 172
19GLUGLUAB-3 - 1681 - 172
29GLUGLUFF-3 - 1681 - 172
110LYSLYSCC-3 - 1671 - 171
210LYSLYSDD-3 - 1671 - 171
111LYSLYSCC-3 - 1671 - 171
211LYSLYSEE-3 - 1671 - 171
112GLUGLUCC-3 - 1681 - 172
212GLUGLUFF-3 - 1681 - 172
113HISHISDD-3 - 1661 - 170
213HISHISEE-3 - 1661 - 170
114LYSLYSDD-3 - 1671 - 171
214LYSLYSFF-3 - 1671 - 171
115GLUGLUEE-3 - 1681 - 172
215GLUGLUFF-3 - 1681 - 172

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

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Components

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


Mass: 19685.209 Da / Num. of mol.: 6 / Mutation: Q61H
Source method: isolated from a genetically manipulated source
Details: KRAS169 Q61H GppNHp / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / 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


Mass: 522.196 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical
ChemComp-CVK / 4-(2,3-dihydro-1,4-benzodioxin-5-yl)-~{N}-[3-[(dimethylamino)methyl]phenyl]-2-methoxy-aniline


Mass: 390.475 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H26N2O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / 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: 2.52 Å3/Da / Density % sol: 51.14 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 8-15% w/v Polyethylene glycol 3350 and 0.2M lithium citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Apr 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.2→94.49 Å / Num. obs: 65992 / % possible obs: 99.2 % / Redundancy: 4.5 % / CC1/2: 0.985 / Rmerge(I) obs: 0.151 / Rpim(I) all: 0.119 / Rrim(I) all: 0.193 / Net I/σ(I): 5
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.78 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 2888 / CC1/2: 0.51 / Rpim(I) all: 0.61 / Rrim(I) all: 0.99 / % possible all: 87.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→94.49 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.93 / SU B: 9.28 / SU ML: 0.211 / Cross valid method: THROUGHOUT / ESU R: 0.303 / ESU R Free: 0.214 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24915 3033 5 %RANDOM
Rwork0.22582 ---
obs0.22698 57318 99.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.747 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0.01 Å2-0 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.2→94.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7970 0 314 58 8342
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0198538
X-RAY DIFFRACTIONr_bond_other_d0.0020.027745
X-RAY DIFFRACTIONr_angle_refined_deg1.6981.99811598
X-RAY DIFFRACTIONr_angle_other_deg0.97317928
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.71251030
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.13324.307404
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.744151452
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7271558
X-RAY DIFFRACTIONr_chiral_restr0.0930.21282
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.029434
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021756
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_it3.7354.1714090
X-RAY DIFFRACTIONr_mcbond_other3.7344.174089
X-RAY DIFFRACTIONr_mcangle_it5.6746.235112
X-RAY DIFFRACTIONr_mcangle_other5.6746.2315113
X-RAY DIFFRACTIONr_scbond_it5.3474.9824448
X-RAY DIFFRACTIONr_scbond_other5.3464.9834449
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.4327.1986481
X-RAY DIFFRACTIONr_long_range_B_refined10.89748.8229123
X-RAY DIFFRACTIONr_long_range_B_other10.89748.8239124
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)
11B104560.07
12A104560.07
21B103360.04
22C103360.04
31B102380.05
32D102380.05
41B103920.07
42E103920.07
51B104600.05
52F104600.05
61A103580.06
62C103580.06
71A103980.06
72D103980.06
81A103920.08
82E103920.08
91A105380.07
92F105380.07
101C102880.05
102D102880.05
111C103880.05
112E103880.05
121C104660.05
122F104660.05
131D104120.07
132E104120.07
141D105220.06
142F105220.06
151E106000.06
152F106000.06
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 235 -
Rwork0.347 4195 -
obs--99.98 %

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