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- PDB-6h47: Human KRAS in complex with darpin K19 -

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Basic information

Entry
Database: PDB / ID: 6h47
TitleHuman KRAS in complex with darpin K19
Components
  • GTPase KRas
  • darpin K19
KeywordsSIGNALING PROTEIN / GTP-ASE / darpin / KRAS signalling
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
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 / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.7 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 ...citation / citation_author / pdbx_database_proc / pdbx_seq_map_depositor_info
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 / _pdbx_seq_map_depositor_info.one_letter_code / _pdbx_seq_map_depositor_info.one_letter_code_mod

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: darpin K19
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1596
Polymers38,7752
Non-polymers3844
Water3,603200
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2590 Å2
ΔGint-54 kcal/mol
Surface area14430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.829, 85.829, 227.122
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-398-

HOH

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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 K19


Mass: 19566.031 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-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 200 / 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: 3.11 Å3/Da / Density % sol: 60.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.5-1.0M lithium sulfate 0.5-1.0M ammonium sulfate 100mM tri-solium citrate pH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.697→113.561 Å / Num. obs: 55734 / % possible obs: 100 % / Redundancy: 16.5 % / CC1/2: 1 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.018 / Net I/σ(I): 30
Reflection shellResolution: 1.697→1.726 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.656 / Num. unique obs: 2738 / CC1/2: 0.795 / Rpim(I) all: 0.343 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementResolution: 1.7→74.33 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.957 / SU B: 3.2 / SU ML: 0.053 / Cross valid method: THROUGHOUT / ESU R: 0.082 / ESU R Free: 0.079 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20777 2818 5.1 %RANDOM
Rwork0.19207 ---
obs0.19287 52806 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30.509 Å2
Baniso -1Baniso -2Baniso -3
1-0.38 Å20.19 Å20 Å2
2--0.38 Å2-0 Å2
3----1.23 Å2
Refinement stepCycle: 1 / Resolution: 1.7→74.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2348 0 20 200 2568
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192420
X-RAY DIFFRACTIONr_bond_other_d0.0020.022246
X-RAY DIFFRACTIONr_angle_refined_deg1.141.9593280
X-RAY DIFFRACTIONr_angle_other_deg0.89435189
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9025306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.70524.505111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.61215417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4991515
X-RAY DIFFRACTIONr_chiral_restr0.0640.2378
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022698
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02473
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_it0.6961.9741221
X-RAY DIFFRACTIONr_mcbond_other0.6961.9721220
X-RAY DIFFRACTIONr_mcangle_it1.2152.9451522
X-RAY DIFFRACTIONr_mcangle_other1.2152.9471523
X-RAY DIFFRACTIONr_scbond_it0.8672.1531199
X-RAY DIFFRACTIONr_scbond_other0.8432.1141184
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.4163.1241733
X-RAY DIFFRACTIONr_long_range_B_refined4.55824.2062653
X-RAY DIFFRACTIONr_long_range_B_other4.31923.6162616
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.697→1.741 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 214 -
Rwork0.29 3794 -
obs--99.88 %
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)
11.07090.5414-0.2112.1226-0.37472.19560.0334-0.1274-0.03550.1993-0.01850.08520.008-0.0623-0.01490.0408-0.0060.00890.02520.01360.0606-28.495410.993410.2971
24.1031-0.728-0.3291.8501-0.04931.92160.0392-0.11230.1960.05690.01910.0261-0.22570.0278-0.05830.056-0.00570.02450.0049-0.0040.0284-21.098832.9082-3.1098
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 166
2X-RAY DIFFRACTION2B0 - 154

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