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- PDB-7yv1: Human K-Ras G12D (GDP-bound) in complex with cyclic peptide inhib... -

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Basic information

Entry
Database: PDB / ID: 7yv1
TitleHuman K-Ras G12D (GDP-bound) in complex with cyclic peptide inhibitor LUNA18 and KA30L Fab
Components
  • Isoform 2B of GTPase KRas
  • KA30L Fab H-chain
  • KA30L Fab L-chain
  • LUNA18
KeywordsSIGNALING PROTEIN / K-RAS / CYCLIC PEPTIDE / ONCOLOGY / SIGNALING PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / positive regulation of glial cell proliferation / 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 / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / 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 / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / 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 / liver development / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / RAF activation / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / visual learning / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Negative regulation of MAPK 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 / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.454 Å
AuthorsIrie, M. / Fukami, T.A. / Matsuo, A. / Saka, K. / Nishimura, M. / Saito, H. / Torizawa, T. / Tanada, M. / Ohta, A.
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 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / citation / pdbx_validate_torsion / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _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 / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 2.1Nov 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
H: KA30L Fab H-chain
L: KA30L Fab L-chain
I: LUNA18
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,4336
Polymers68,9654
Non-polymers4682
Water19,3121072
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7010 Å2
ΔGint-54 kcal/mol
Surface area26550 Å2
Unit cell
Length a, b, c (Å)65.617, 90.373, 116.810
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Antibody , 2 types, 2 molecules HL

#2: Antibody KA30L Fab H-chain


Mass: 24116.066 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#3: Antibody KA30L Fab L-chain


Mass: 23242.715 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)

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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
#4: Protein/peptide LUNA18


Mass: 1455.696 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 3 types, 1074 molecules

#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1072 / 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: 2.51 Å3/Da / Density % sol: 50.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 2.0 %v/v Tacsimate (pH 5.0), 0.1 M tri-Sodium citrate (pH 5.6), 16.0 %w/v Polyethylene glycol 3,350, and 25 %v/v Ethylene glycerol as a cryoprotectant

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.454→58.41 Å / Num. obs: 97915 / % possible obs: 90.3 % / Redundancy: 9.35 % / CC1/2: 0.997 / Rmerge(I) obs: 0.1335 / Rpim(I) all: 0.0442 / Rrim(I) all: 0.141 / Net I/σ(I): 16.42
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
4.347-58.40510.490.051643.735136351363489548950.9980.01660.054299.9
3.428-4.34710.940.058942.025357453574489648960.9980.01860.0618100
2.983-3.42810.770.088336.55274252742489548950.9960.02810.0929100
2.705-2.98311.010.130231.065392553925489748970.9920.04120.136799.9
2.508-2.70511.250.160426.95506355063489548950.990.05040.168499.9
2.357-2.50810.30.177423.335043650436489648960.990.05830.187199.9
2.236-2.35710.280.192421.355034550345489648960.9930.06270.202799.9
2.137-2.23610.530.203819.325154451544489548950.9930.0660.2145100
2.054-2.13710.560.210517.135173351733489748970.9940.06790.2214100
1.982-2.0539.740.215314.224767647676489548950.9940.07250.2275100
1.919-1.9829.490.254411.564647246472489648960.9910.08770.2696100
1.863-1.9199.890.3199.244840248402489648960.9860.10830.3374100
1.813-1.86310.140.36617.664965049650489648960.980.12270.3867100
1.768-1.81310.380.45886.25078650786489548950.9660.15160.483898.9
1.726-1.7689.310.54094.724555845558489348930.9510.18880.574197.5
1.685-1.7268.130.61983.863984739847489948990.9250.22940.663588.7
1.64-1.6857.230.73643.23539435394489548950.8460.28890.795877.2
1.591-1.646.470.84342.683167631676489748970.7320.35110.920468.8
1.535-1.5915.470.97222.182678726787489448940.5150.44581.078761.6
1.454-1.5354.581.28441.552241422414489748970.2270.65441.455151.2

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (20-APR-2021)refinement
autoPROC1.1.7data processing
XDSJan 26, 2018data reduction
Aimless0.7.4data scaling
STARANISO2.3.46data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7VO2

7vo2
PDB Unreleased entry


Resolution: 1.454→58.41 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.889 / SU R Cruickshank DPI: 0.104 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.118 / SU Rfree Blow DPI: 0.115 / SU Rfree Cruickshank DPI: 0.106
RfactorNum. reflection% reflectionSelection details
Rfree0.2772 4912 5.02 %RANDOM
Rwork0.2377 ---
obs0.2397 97915 80 %-
Displacement parametersBiso max: 76.89 Å2 / Biso mean: 15.17 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-0.5215 Å20 Å20 Å2
2---0.2787 Å20 Å2
3----0.2428 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 1.454→58.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4715 0 32 1072 5819
Biso mean--7.51 29.51 -
Num. residues----615
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1688SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes849HARMONIC5
X-RAY DIFFRACTIONt_it4904HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion649SEMIHARMONIC5
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_contact5169SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4904HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6702HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion4.02
X-RAY DIFFRACTIONt_other_torsion14.98
LS refinement shellResolution: 1.454→1.49 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2916 95 4.85 %
Rwork0.3045 1864 -
obs--21.08 %

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