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- PDB-8cpr: G13D mutant of KRAS4b (2-169) bound to GDP with the switch-I in f... -

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Basic information

Entry
Database: PDB / ID: 8cpr
TitleG13D mutant of KRAS4b (2-169) bound to GDP with the switch-I in fully open conformation crystallized in sodium potassium phosphate buffer
ComponentsGTPase KRas, N-terminally processed
KeywordsONCOPROTEIN / KRAS / colorectal cancer / RAS signalling / cancer stem cells / RAS-driven metastasis / KRAS structure / KRAS mutations
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 / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / SHC-mediated cascade:FGFR2 / 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 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / 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 / Signaling by CSF1 (M-CSF) in myeloid cells / Regulation of RAS by GAPs / 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 / MAPK cascade / 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 / mitochondrial outer membrane / Ras protein signal transduction / 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 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsMoche, M. / Jungholm, O. / Strandback, E. / Ampah-Korsah, H. / Nyman, T. / Orwar, O.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Other governmentC33001013 Sweden
CitationJournal: Sci Rep / Year: 2024
Title: Novel druggable space in human KRAS G13D discovered using structural bioinformatics and a P-loop targeting monoclonal antibody.
Authors: Jungholm, O. / Trkulja, C. / Moche, M. / Srinivasa, S.P. / Christakopoulou, M.N. / Davidson, M. / Reymer, A. / Jardemark, K. / Fogaca, R.L. / Ashok, A. / Jeffries, G. / Ampah-Korsah, H. / ...Authors: Jungholm, O. / Trkulja, C. / Moche, M. / Srinivasa, S.P. / Christakopoulou, M.N. / Davidson, M. / Reymer, A. / Jardemark, K. / Fogaca, R.L. / Ashok, A. / Jeffries, G. / Ampah-Korsah, H. / Strandback, E. / Andrell, J. / Nyman, T. / Nouairia, G. / Orwar, O.
History
DepositionMar 3, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2024Group: 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.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas, N-terminally processed
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9293
Polymers19,4631
Non-polymers4662
Water2,072115
1
A: GTPase KRas, N-terminally processed
hetero molecules

A: GTPase KRas, N-terminally processed
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8586
Polymers38,9262
Non-polymers9324
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Buried area3260 Å2
ΔGint-33 kcal/mol
Surface area16310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.413, 76.413, 55.862
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number150
Space group name H-MP321

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Components

#1: Protein GTPase KRas, N-terminally processed


Mass: 19462.906 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 (E. coli) / References: UniProt: P01116
#2: 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
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / 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: 2.43 Å3/Da / Density % sol: 49.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 1.4 M Na/K Phosphate pH around 8.8 OR 0.9 M Na/K Phosphate pH 9.1 (sodium potassium phosphate), 0.5 M Na/K Phosphate pH 8.3

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Data collection

DiffractionMean temperature: 293 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.976254 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 2.001→42.686 Å / Num. obs: 9569 / % possible obs: 73.3 % / Redundancy: 9.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.172 / Rpim(I) all: 0.059 / Rrim(I) all: 0.182 / Net I/σ(I): 8.6
Reflection shellResolution: 2.001→2.146 Å / Rmerge(I) obs: 1.155 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 478 / CC1/2: 0.775 / Rpim(I) all: 0.394 / Rrim(I) all: 1.222

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
STARANISOdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→42.72 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.91 / SU B: 6.303 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.33 / ESU R Free: 0.239 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24809 481 5 %RANDOM
Rwork0.17949 ---
obs0.18288 9087 73.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.579 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å20.1 Å20 Å2
2--0.19 Å2-0 Å2
3----0.63 Å2
Refinement stepCycle: 1 / Resolution: 2→42.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1358 0 29 115 1502
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0121574
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161398
X-RAY DIFFRACTIONr_angle_refined_deg1.4531.6592156
X-RAY DIFFRACTIONr_angle_other_deg0.4971.5683282
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1285201
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.885516
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.510287
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0640.2236
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021895
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02319
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_it2.6912.941756
X-RAY DIFFRACTIONr_mcbond_other2.6842.94756
X-RAY DIFFRACTIONr_mcangle_it4.2194.382973
X-RAY DIFFRACTIONr_mcangle_other4.2184.388974
X-RAY DIFFRACTIONr_scbond_it3.713.479818
X-RAY DIFFRACTIONr_scbond_other3.7143.483816
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.0315.0311184
X-RAY DIFFRACTIONr_long_range_B_refined9.55258.8287040
X-RAY DIFFRACTIONr_long_range_B_other9.4558.1266942
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.001→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 7 -
Rwork0.311 133 -
obs--14.57 %

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