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- PDB-6h46: Human KRAS in complex with darpin K13 -

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Basic information

Entry
Database: PDB / ID: 6h46
TitleHuman KRAS in complex with darpin K13
Components
  • GTPase KRas
  • darpin K13
KeywordsSIGNALING PROTEIN / GTP-ASE / darpin / KRAS signalling
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / 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 / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / 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 / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / 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 / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / negative regulation of neuron apoptotic process / Ras protein signal transduction / mitochondrial outer membrane / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Ankyrin repeat-containing domain / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat ...Ankyrin repeat-containing domain / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Small GTP-binding protein domain / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsDebreczeni, J.E. / Bery, N. / Legg, S. / Breed, J. / Embrey, K. / Stubbs, C. / Kolasinska-Zwierz, P. / Barrett, N. / Marwood, R. / Watson, J. ...Debreczeni, J.E. / Bery, N. / Legg, S. / Breed, J. / Embrey, K. / Stubbs, C. / Kolasinska-Zwierz, P. / Barrett, N. / Marwood, R. / Watson, J. / Tart, J. / Overman, R. / Miller, A. / Phillips, C. / Minter, R. / Rabbitts, T.H.
CitationJournal: Nat Commun / Year: 2019
Title: KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe.
Authors: Bery, N. / Legg, S. / Debreczeni, J. / Breed, J. / Embrey, K. / Stubbs, C. / Kolasinska-Zwierz, P. / Barrett, N. / Marwood, R. / Watson, J. / Tart, J. / Overman, R. / Miller, A. / Phillips, ...Authors: Bery, N. / Legg, S. / Debreczeni, J. / Breed, J. / Embrey, K. / Stubbs, C. / Kolasinska-Zwierz, P. / Barrett, N. / Marwood, R. / Watson, J. / Tart, J. / Overman, R. / Miller, A. / Phillips, C. / Minter, R. / Rabbitts, T.H.
History
DepositionJul 20, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
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.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: darpin K13
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6765
Polymers36,0412
Non-polymers6353
Water4,035224
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2930 Å2
ΔGint-34 kcal/mol
Surface area14160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.295, 79.295, 130.025
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11B-201-

SO4

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Components

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


Mass: 19208.643 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P01116
#2: Protein darpin K13


Mass: 16832.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21 (bacteria)
#3: 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
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.84 Å3/Da / Density % sol: 56.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.5-1.0M lithium sulfate 0.5-1.0M ammonium sulfate 100mM tri-sodium citrate pH5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 21, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.22→51.5 Å / Num. obs: 21240 / % possible obs: 99.9 % / Redundancy: 13.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.039 / Net I/σ(I): 20.9
Reflection shellResolution: 2.22→2.28 Å / Redundancy: 12.1 % / Rmerge(I) obs: 0.653 / Mean I/σ(I) obs: 0.885 / Num. unique obs: 1532 / CC1/2: 0.885 / Rpim(I) all: 0.277 / % possible all: 99.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.22→23.59 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.917 / SU B: 9.646 / SU ML: 0.134 / Cross valid method: THROUGHOUT / ESU R: 0.231 / ESU R Free: 0.194 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23039 1046 5 %RANDOM
Rwork0.18313 ---
obs0.18545 20043 99.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 34.531 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20 Å2
2---0.01 Å20 Å2
3---0.02 Å2
Refinement stepCycle: 1 / Resolution: 2.22→23.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2507 0 38 224 2769
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192603
X-RAY DIFFRACTIONr_bond_other_d0.0020.022391
X-RAY DIFFRACTIONr_angle_refined_deg1.2941.9683539
X-RAY DIFFRACTIONr_angle_other_deg0.93935542
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3485328
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.20425.124121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.02715442
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.241513
X-RAY DIFFRACTIONr_chiral_restr0.070.2405
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022908
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02501
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_it0.5571.9031302
X-RAY DIFFRACTIONr_mcbond_other0.5491.9011301
X-RAY DIFFRACTIONr_mcangle_it0.9972.8481627
X-RAY DIFFRACTIONr_mcangle_other0.9972.8491628
X-RAY DIFFRACTIONr_scbond_it0.5241.9941301
X-RAY DIFFRACTIONr_scbond_other0.5241.9931293
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.9142.9641898
X-RAY DIFFRACTIONr_long_range_B_refined4.28123.462922
X-RAY DIFFRACTIONr_long_range_B_other4.17923.0142887
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.22→2.277 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.302 77 -
Rwork0.211 1423 -
obs--97.91 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.8206-0.1677-0.71992.8004-0.13123.654-0.0719-0.22890.47790.21480.0381-0.1724-0.37320.15160.03370.0908-0.0248-0.07260.0515-0.0180.1321.5583-1.236714.5701
24.19930.56841.10082.16740.53392.2489-0.02090.1123-0.1614-0.0653-0.01150.24220.0818-0.05180.03240.0130.0080.00360.02970.00990.054715.2608-24.331316.5616
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 166
2X-RAY DIFFRACTION2B1 - 156

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