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- PDB-7yuz: Human K-Ras G12D (GDP-bound) in complex with cyclic peptide inhib... -

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Basic information

Entry
Database: PDB / ID: 7yuz
TitleHuman K-Ras G12D (GDP-bound) in complex with cyclic peptide inhibitor AP8784
Components
  • AP8784
  • Isoform 2B of GTPase KRas
KeywordsSIGNALING PROTEIN/INHIBITOR / ONCOLOGY / 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
GUANOSINE-5'-DIPHOSPHATE / IODIDE ION / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.878 Å
AuthorsIrie, M. / Fukami, T.A. / Tanada, M. / Ohta, A. / Torizawa, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: J.Am.Chem.Soc. / Year: 2023
Title: Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.
Authors: Ohta, A. / Tanada, M. / Shinohara, S. / Morita, Y. / Nakano, K. / Yamagishi, Y. / Takano, R. / Kariyuki, S. / Iida, T. / Matsuo, A. / Ozeki, K. / Emura, T. / Sakurai, Y. / Takano, K. / ...Authors: Ohta, A. / Tanada, M. / Shinohara, S. / Morita, Y. / Nakano, K. / Yamagishi, Y. / Takano, R. / Kariyuki, S. / Iida, T. / Matsuo, A. / Ozeki, K. / Emura, T. / Sakurai, Y. / Takano, K. / Higashida, A. / Kojima, M. / Muraoka, T. / Takeyama, R. / Kato, T. / Kimura, K. / Ogawa, K. / Ohara, K. / Tanaka, S. / Kikuchi, Y. / Hisada, N. / Hayashi, R. / Nishimura, Y. / Nomura, K. / Tachibana, T. / Irie, M. / Kawada, H. / Torizawa, T. / Murao, N. / Kotake, T. / Tanaka, M. / Ishikawa, S. / Miyake, T. / Tamiya, M. / Arai, M. / Chiyoda, A. / Akai, S. / Sase, H. / Kuramoto, S. / Ito, T. / Shiraishi, T. / Kojima, T. / Iikura, H.
#1: Journal: J.Am.Chem.Soc. / Year: 2023
Title: Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor
Authors: Tanada, M. / Tamiya, M. / Matsuo, A. / Chiyoda, A. / Takano, K. / Ito, T. / Irie, M. / Kotake, T. / Takeyama, R. / Kawada, H. / Hayashi, R. / Ishikawa, S. / Nomura, K. / Furuichi, N. / ...Authors: Tanada, M. / Tamiya, M. / Matsuo, A. / Chiyoda, A. / Takano, K. / Ito, T. / Irie, M. / Kotake, T. / Takeyama, R. / Kawada, H. / Hayashi, R. / Ishikawa, S. / Nomura, K. / Furuichi, N. / Morita, Y. / Kage, M. / Hashimoto, S. / Nii, K. / Sase, H. / Ohara, K. / Ohta, A. / Kuramoto, S. / Nishimura, Y. / Iikura, H. / Shiraishi, T.
History
DepositionAug 18, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Nov 15, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _citation.pdbx_database_id_PubMed / _citation.title / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Nov 22, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
I: AP8784
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1815
Polymers21,5862
Non-polymers5943
Water54030
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2200 Å2
ΔGint-35 kcal/mol
Surface area8020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.012, 66.012, 86.330
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AI

#1: Protein Isoform 2B of GTPase KRas


Mass: 20150.582 Da / Num. of mol.: 1 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / Strain (production host): Tuner(DE3)pLacI / References: UniProt: P01116
#2: Protein/peptide AP8784


Mass: 1435.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 33 molecules

#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 2.49 Å3/Da / Density % sol: 50.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Ammonium iodide, 20.0 %w/v Polyethylene glycol 3,350, and 25%v/v Ethylene glycol as a cryoprotectant

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.000006 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000006 Å / Relative weight: 1
ReflectionResolution: 1.878→34.45 Å / Num. obs: 12671 / % possible obs: 94 % / Redundancy: 19.28 % / CC1/2: 0.999 / Rmerge(I) obs: 0.0505 / Rpim(I) all: 0.0121 / Rrim(I) all: 0.052 / Net I/σ(I): 23.58
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
5.978-34.44816.550.033966.9610494104946346340.9990.220.00840.0351.41001001001001009.97100
4.695-5.97815.990.038861.71101381013863463410.2430.00990.04011.2131001001001001009.01100
4.079-4.69517.770.038262.3411283112836356350.999-0.2310.00910.03930.97310099.810099.81009.7999.8
3.696-4.07918.330.043756.7711550115506306300.999-0.3520.01030.04490.8541001001001001009.99100
3.417-3.69619.050.05149.5912098120986356350.9990.0080.01190.05240.88510010010010010010.43100
3.212-3.41719.480.060641.0112387123876366360.998-0.1190.0140.06220.81610010010010010010.45100
3.045-3.21218.060.082730.1111397113976316310.998-0.0460.020.08510.771001001001001009.7100
2.909-3.04518.220.113823.2311553115536346340.998-0.0140.02740.11710.7891001001001001009.75100
2.794-2.90919.60.16717.3612409124096336330.9950.0380.03860.17150.75810010010010010010.48100
2.697-2.79420.140.208914.412746127466336330.996-0.0610.04780.21440.69410010010010010010.7100
2.609-2.69720.50.279810.8212958129586326320.9940.0510.06310.28690.69110010010010010010.84100
2.529-2.60920.530.37468.3313018130186346340.9920.0180.08430.38410.66710010010010010010.89100
2.462-2.52920.820.48396.6113281132816386380.988-0.0860.10820.49610.63410010010010010011.05100
2.402-2.46221.090.62325.413224132246276270.986-0.0110.13870.63870.66799.899.899.899.899.811.1499.8
2.346-2.40220.720.78974.1813155131556356350.981-0.0430.17710.80970.61999.699.799.699.799.611.0599.7
2.295-2.34621.190.92533.5713522135226386380.98-0.0460.20480.94810.63699.799.799.799.799.711.1499.7
2.242-2.29521.111.25152.7713297132976306300.9180.0180.27721.28240.64390.989.690.989.690.911.0789.6
2.171-2.24219.431.16722.6812374123746376370.892-0.0390.27011.19870.64169.470.369.458.857.910.3170.3
2.079-2.17119.041.35162.2711974119746296290.792-0.0280.31681.38910.63377.478.477.43937.210.2478.4
1.878-2.07918.051.83021.5311481114816366360.664-0.0210.44171.88430.61169.369.169.313.512.39.8769.1

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (20-APR-2021)refinement
autoPROC1.1.7data processing
XDSJan 31, 2020data reduction
Aimless0.7.7data scaling
STARANISO2.3.63data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.878→34.45 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.925 / SU R Cruickshank DPI: 0.255 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.255 / SU Rfree Blow DPI: 0.214 / SU Rfree Cruickshank DPI: 0.215
RfactorNum. reflection% reflectionSelection details
Rfree0.2985 623 4.92 %RANDOM
Rwork0.2589 ---
obs0.2611 12671 69.4 %-
Displacement parametersBiso max: 96.69 Å2 / Biso mean: 56.01 Å2 / Biso min: 30.07 Å2
Baniso -1Baniso -2Baniso -3
1-0.1406 Å20 Å20 Å2
2--0.1406 Å20 Å2
3----0.2813 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 1.878→34.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1409 0 35 30 1474
Biso mean--49.8 50.58 -
Num. residues----181
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d527SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes273HARMONIC5
X-RAY DIFFRACTIONt_it1471HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion196SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1236SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1471HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg2007HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion3.1
X-RAY DIFFRACTIONt_other_torsion16.57
LS refinement shellResolution: 1.88→2.04 Å / Rfactor Rfree error: 0 / Total num. of bins used: 32
RfactorNum. reflection% reflection
Rfree0.5193 14 3.42 %
Rwork0.3231 395 -
all0.3293 409 -
obs--10.3 %

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