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- PDB-6ziz: CRYSTAL STRUCTURE OF NRAS Q61R IN COMPLEX WITH GTP AND COMPOUND 18 -

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Basic information

Entry
Database: PDB / ID: 6ziz
TitleCRYSTAL STRUCTURE OF NRAS Q61R IN COMPLEX WITH GTP AND COMPOUND 18
ComponentsGTPase NRas
KeywordsHYDROLASE / GTPase
Function / homology
Function and homology information


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 ...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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / 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 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / Tie2 Signaling / positive regulation of endothelial cell proliferation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / 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 / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / 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 / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G protein activity / RAF/MAP kinase cascade / Ras protein signal transduction / Golgi membrane / GTPase activity / Neutrophil degranulation / endoplasmic reticulum membrane / GTP binding / protein-containing complex binding / Golgi apparatus / extracellular exosome / membrane / plasma membrane / cytosol
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 nucleotide triphosphate hydrolases / Rossmann fold ...Small GTPase, Ras-type / Small GTPase Ras domain 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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-EZZ / GUANOSINE-5'-TRIPHOSPHATE / GTPase NRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.785 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:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase NRas
B: GTPase NRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,0208
Polymers39,2832
Non-polymers1,7386
Water5,314295
1
A: GTPase NRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5104
Polymers19,6411
Non-polymers8693
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase NRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5104
Polymers19,6411
Non-polymers8693
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)115.829, 45.790, 86.045
Angle α, β, γ (deg.)90.00, 111.28, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 19641.281 Da / Num. of mol.: 2
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-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#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


Mass: 18.015 Da / Num. of mol.: 295 / 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: 2.71 Å3/Da / Density % sol: 54.55 %
Crystal growTemperature: 278 K / Method: vapor diffusion
Details: Morpheus buffer 1 100mM pH=6.6 Morpheus Monosacharides 14% P550MME_P20K 32%

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Nov 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.785→54.9496 Å / Num. obs: 25105 / % possible obs: 87.6 % / Redundancy: 5 % / Biso Wilson estimate: 23.22 Å2 / Rmerge(I) obs: 0.171 / Rsym value: 0.171 / Net I/σ(I): 7.7
Reflection shellResolution: 1.785→1.986 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.988 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1255 / Rsym value: 0.988 / % possible all: 51.4

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 26data reduction
autoPROC(Version 1.1.7)data scaling
STARANISOdata scaling
BUSTER2.11.7 (3-OCT-2019)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6ZIO

6zio


Resolution: 1.785→54 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.914 / SU R Cruickshank DPI: 0.678 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.234 / SU Rfree Blow DPI: 0.166 / SU Rfree Cruickshank DPI: 0.162
RfactorNum. reflection% reflectionSelection details
Rfree0.2188 1213 4.83 %RANDOM
Rwork0.2075 ---
obs0.2081 25104 62.3 %-
Displacement parametersBiso mean: 27.88 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å2-0.2936 Å2
2--0.4527 Å20 Å2
3----0.4128 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 1.785→54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2703 0 114 295 3112
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0115713HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0810282HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1777SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes927HARMONIC5
X-RAY DIFFRACTIONt_it2926HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.45
X-RAY DIFFRACTIONt_other_torsion16.57
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion380SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4522SEMIHARMONIC4
Refinement TLS params.

L11: 0 °2 / L12: 0 °2 / L13: 0 °2 / L22: 0 °2 / L23: 0 °2 / L33: 0 °2 / S11: 0 Å ° / S12: 0 Å ° / S13: 0 Å ° / S21: 0 Å ° / S22: 0 Å ° / S23: 0 Å ° / S31: 0 Å ° / S32: 0 Å ° / S33: 0 Å ° / T11: 0 Å2 / T12: 0 Å2 / T13: 0 Å2 / T22: 0 Å2 / T23: 0 Å2 / T33: 0 Å2 / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDOrigin x (Å)Origin y (Å)Origin z (Å)
124.3693-0.947737.3527
235.0948-10.78549.7411
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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