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- PDB-6zir: CRYSTAL STRUCTURE OF NRAS (C118S) IN COMPLEX WITH GDP AND COMPOUND 18 -

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Basic information

Entry
Database: PDB / ID: 6zir
TitleCRYSTAL STRUCTURE OF NRAS (C118S) IN COMPLEX WITH GDP AND COMPOUND 18
ComponentsGTPase NRas
KeywordsHYDROLASE / GTPase
Function / homology
Function and homology information


myoblast differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / tertiary granule membrane / RAS signaling downstream of NF1 loss-of-function variants / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling ...myoblast differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / tertiary granule membrane / RAS signaling downstream of NF1 loss-of-function variants / 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 / 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 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / FRS-mediated FGFR3 signaling / 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 / 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 / positive regulation of endothelial cell proliferation / 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 / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / 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 / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / RAF/MAP kinase cascade / Ras protein signal transduction / Golgi membrane / GTPase activity / Neutrophil degranulation / protein-containing complex binding / GTP binding / endoplasmic reticulum membrane / Golgi apparatus / extracellular exosome / membrane / plasma membrane / cytosol
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / 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
Chem-EZZ / GUANOSINE-5'-DIPHOSPHATE / GTPase NRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsKessler, D. / Fischer, G. / Boettcher, J.
CitationJournal: Future Med Chem / Year: 2020
Title: Drugging all RAS isoforms with one pocket.
Authors: Kessler, D. / Bergner, A. / Bottcher, J. / Fischer, G. / Dobel, S. / Hinkel, M. / Mullauer, B. / Weiss-Puxbaum, A. / McConnell, D.B.
History
DepositionJun 26, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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:
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Assembly

Deposited unit
A: GTPase NRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,7476
Polymers19,6121
Non-polymers1,1355
Water3,765209
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-20 kcal/mol
Surface area8000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.806, 103.806, 54.775
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number150
Space group name H-MP321
Components on special symmetry positions
IDModelComponents
11A-414-

HOH

21A-490-

HOH

31A-493-

HOH

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Components

#1: Protein GTPase NRas / Transforming protein N-Ras


Mass: 19612.217 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01111
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine 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-EZZ / (3~{S})-3-[2-[(dimethylamino)methyl]-1~{H}-indol-3-yl]-5-oxidanyl-2,3-dihydroisoindol-1-one


Mass: 321.373 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N3O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 209 / Source method: isolated from a natural source / Formula: H2O
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: 4.34 Å3/Da / Density % sol: 71.68 %
Crystal growTemperature: 278 K / Method: vapor diffusion
Details: 3.7M sodium formate, 2% PEG 3000, 100mM bicine PH=8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Dec 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.9→51.903 Å / Num. obs: 21123 / % possible obs: 85.9 % / Redundancy: 4.2 % / Biso Wilson estimate: 31.5 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 15.8
Reflection shellResolution: 1.9→2.024 Å / Rmerge(I) obs: 1.173 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 4603

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ZIO

6zio


Resolution: 1.9→40 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.127 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.138 / SU Rfree Blow DPI: 0.128 / SU Rfree Cruickshank DPI: 0.122
RfactorNum. reflection% reflectionSelection details
Rfree0.215 1068 5.06 %RANDOM
Rwork0.187 ---
obs0.189 21123 78.2 %-
Displacement parametersBiso mean: 42.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.4449 Å20 Å20 Å2
2--0.4449 Å20 Å2
3----0.8898 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.9→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1295 0 78 208 1581
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081418HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.941927HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d513SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes250HARMONIC5
X-RAY DIFFRACTIONt_it1418HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion17.98
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion183SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies2HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1837SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.99 Å
RfactorNum. reflection% reflection
Rfree0.2481 -5.29 %
Rwork-448 -
Refinement TLS params.Method: refined / Origin x: 48.3116 Å / Origin y: -8.5093 Å / Origin z: 14.4866 Å
111213212223313233
T0.0163 Å20.0067 Å2-0.0366 Å2--0.1415 Å20.0165 Å2---0.1743 Å2
L1.4155 °20.31 °20.0975 °2-7.5541 °20.684 °2--1.4169 °2
S-0.0931 Å °0.0843 Å °-0.0739 Å °-0.5861 Å °0.061 Å °0.1104 Å °-0.3629 Å °-0.0234 Å °0.0321 Å °
Refinement TLS groupSelection details: { A|* }

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