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- PDB-7ny8: Affimer K69 - KRAS protein complex -

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Basic information

Entry
Database: PDB / ID: 7ny8
TitleAffimer K69 - KRAS protein complex
Components
  • Affimer K69
  • GTPase KRas
KeywordsPROTEIN BINDING / Protein complex / Affimer / KRAS / Inhibitor
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 / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / 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 / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / 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 / RAF activation / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / 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
Nuclear Transport Factor 2; Chain: A, - #10 / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Nuclear Transport Factor 2; Chain: A, / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases ...Nuclear Transport Factor 2; Chain: A, - #10 / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Nuclear Transport Factor 2; Chain: A, / 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 / Roll / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / 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: 1.8 Å
AuthorsTurner, A.L. / Trinh, C.H. / Haza, K.Z. / Rao, A. / Martin, H.L. / Tiede, C. / Edwards, T.A. / McPherson, M.J. / Tomlinson, D.C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/P019188/1 United Kingdom
CitationJournal: Nat Commun / Year: 2021
Title: RAS-inhibiting biologics identify and probe druggable pockets including an SII-alpha 3 allosteric site.
Authors: Haza, K.Z. / Martin, H.L. / Rao, A. / Turner, A.L. / Saunders, S.E. / Petersen, B. / Tiede, C. / Tipping, K. / Tang, A.A. / Ajayi, M. / Taylor, T. / Harvey, M. / Fishwick, K.M. / Adams, T.L. ...Authors: Haza, K.Z. / Martin, H.L. / Rao, A. / Turner, A.L. / Saunders, S.E. / Petersen, B. / Tiede, C. / Tipping, K. / Tang, A.A. / Ajayi, M. / Taylor, T. / Harvey, M. / Fishwick, K.M. / Adams, T.L. / Gaule, T.G. / Trinh, C.H. / Johnson, M. / Breeze, A.L. / Edwards, T.A. / McPherson, M.J. / Tomlinson, D.C.
History
DepositionMar 21, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Affimer K69
D: Affimer K69
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7858
Polymers63,8504
Non-polymers9354
Water4,648258
1
A: GTPase KRas
C: Affimer K69
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3934
Polymers31,9252
Non-polymers4682
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2520 Å2
ΔGint-25 kcal/mol
Surface area12310 Å2
MethodPISA
2
B: GTPase KRas
D: Affimer K69
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3934
Polymers31,9252
Non-polymers4682
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2260 Å2
ΔGint-27 kcal/mol
Surface area13890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.008, 168.775, 39.653
Angle α, β, γ (deg.)90.000, 92.700, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 19295.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) / References: UniProt: P01116
#2: Protein Affimer K69


Mass: 12629.335 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3)
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.29 Å3/Da / Density % sol: 39.77 % / Description: 46.20%
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M imidazole, 0.1M MES monohydrate, 20% w/v PEG 500 MME, 10% w/v PEG 20000, 0.12M 1,6-hexanediol, 0.12M 1,2-propanediol, 0.12M 1,4-butanediol, 0.12M 1-butanol, 0.12M 2-propanol, 0.12M 1,3-propanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Oct 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.8→168.77 Å / Num. obs: 47236 / % possible obs: 100 % / Redundancy: 6.9 % / Biso Wilson estimate: 25.2 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.03 / Rrim(I) all: 0.078 / Net I/σ(I): 19.3
Reflection shellResolution: 1.8→1.83 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.734 / Num. unique obs: 2336 / CC1/2: 0.821 / Rpim(I) all: 0.3 / Rrim(I) all: 0.794 / % possible all: 100

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Processing

Software
NameVersionClassification
DIALS3.1.3data scaling
PHASER2.8.3phasing
REFMAC5.8.0258refinement
DIALS3.1.3data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OBE, 4N6T

4obe

4n6t


Resolution: 1.8→84.53 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.951 / SU B: 6.913 / SU ML: 0.094 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.314 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2097 2378 5 %RANDOM
Rwork0.154 ---
obs0.1568 44810 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.8 Å2 / Biso mean: 29.893 Å2 / Biso min: 14.32 Å2
Baniso -1Baniso -2Baniso -3
1-1.03 Å20 Å2-0.05 Å2
2---1.21 Å20 Å2
3---0.18 Å2
Refinement stepCycle: final / Resolution: 1.8→84.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4253 0 58 258 4569
Biso mean--28.2 36.06 -
Num. residues----523
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0134402
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174024
X-RAY DIFFRACTIONr_angle_refined_deg1.3141.6695919
X-RAY DIFFRACTIONr_angle_other_deg1.2231.5959339
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5745518
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.55222.913254
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.33415805
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7981528
X-RAY DIFFRACTIONr_chiral_restr0.0520.2554
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024850
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02930
X-RAY DIFFRACTIONr_rigid_bond_restr1.30438426
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.28 177 -
Rwork0.204 3310 -
all-3487 -
obs--100 %

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