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- PDB-6zj0: CRYSTAL STRUCTURE OF HRAS-G12D IN COMPLEX WITH GCP AND COMPOUND 18 -

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Basic information

Entry
Database: PDB / ID: 6zj0
TitleCRYSTAL STRUCTURE OF HRAS-G12D IN COMPLEX WITH GCP AND COMPOUND 18
ComponentsGTPase HRas
KeywordsHYDROLASE / GTPase
Function / homology
Function and homology information


GTPase complex / oncogene-induced cell senescence / positive regulation of ruffle assembly / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / negative regulation of GTPase activity / T-helper 1 type immune response / positive regulation of wound healing / positive regulation of miRNA metabolic process / defense response to protozoan / Signaling by RAS GAP mutants ...GTPase complex / oncogene-induced cell senescence / positive regulation of ruffle assembly / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / negative regulation of GTPase activity / T-helper 1 type immune response / positive regulation of wound healing / positive regulation of miRNA metabolic process / defense response to protozoan / 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 / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / positive regulation of protein targeting to membrane / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / adipose tissue development / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / : / Schwann cell development / 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 / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / 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 / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EPHB-mediated forward signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / Ras activation upon Ca2+ influx through NMDA receptor / 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 / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / intrinsic apoptotic signaling pathway / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / positive regulation of GTPase activity / VEGFR2 mediated cell proliferation / positive regulation of epithelial cell proliferation / regulation of actin cytoskeleton organization / FCERI mediated MAPK activation / animal organ morphogenesis / positive regulation of JNK cascade / Signaling by ERBB2 TMD/JMD mutants / RAF activation / regulation of long-term neuronal synaptic plasticity / positive regulation of MAP kinase activity / 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 / cellular response to gamma radiation / Regulation of RAS by GAPs / endocytosis / Negative regulation of MAPK pathway / RAS processing / 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 / chemotaxis / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / positive regulation of type II interferon production / positive regulation of fibroblast proliferation / insulin receptor signaling pathway / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
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 / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GTPase HRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.763 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 HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8815
Polymers18,9901
Non-polymers8914
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint-17 kcal/mol
Surface area7960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.075, 93.075, 55.256
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-334-

HOH

21A-342-

HOH

31A-460-

HOH

41A-463-

HOH

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Components

#1: Protein GTPase HRas / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


Mass: 18990.279 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01112
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*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.: 1 / Source method: obtained synthetically / Formula: C19H19N3O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 3.64 Å3/Da / Density % sol: 66.19 %
Crystal growTemperature: 278 K / Method: vapor diffusion / Details: 30% PEG400, 200mM MgCl2, 100mM TRIS PH=8,5

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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 PILATUS 2M / Detector: PIXEL / Date: Mar 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.763→80.61 Å / Num. obs: 22394 / % possible obs: 81.4 % / Redundancy: 14.9 % / Biso Wilson estimate: 38.08 Å2 / Rmerge(I) obs: 0.054 / Rsym value: 0.054 / Net I/σ(I): 27.9
Reflection shellResolution: 1.764→1.905 Å / Redundancy: 14.7 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1119 / CC1/2: 0.524 / % possible all: 20

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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 (17-DEC-2019)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3L8Z

3l8z


Resolution: 1.763→80.61 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.945 / SU R Cruickshank DPI: 0.138 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.122 / SU Rfree Blow DPI: 0.117 / SU Rfree Cruickshank DPI: 0.112
RfactorNum. reflection% reflectionSelection details
Rfree0.2276 1119 5 %RANDOM
Rwork0.1984 ---
obs0.1999 22394 81.2 %-
Displacement parametersBiso mean: 52.4 Å2
Baniso -1Baniso -2Baniso -3
1--0.3162 Å20 Å20 Å2
2---0.3162 Å20 Å2
3---0.6325 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.763→80.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1290 0 58 172 1520
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082673HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.934803HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d828SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes429HARMONIC5
X-RAY DIFFRACTIONt_it1371HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.55
X-RAY DIFFRACTIONt_other_torsion15.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion176SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2263SEMIHARMONIC4
Refinement TLS params.Method: refined / Origin x: -27.3276 Å / Origin y: 34.3675 Å / Origin z: 11.967 Å
111213212223313233
T-0.1228 Å2-0.0503 Å20.0009 Å2-0.0035 Å2-0.0024 Å2---0.1322 Å2
L4.7398 °21.8776 °2-0.4512 °2-2.6089 °2-0.7027 °2--1.9008 °2
S0.1819 Å °-0.6404 Å °0.0675 Å °0.1612 Å °-0.182 Å °0.0678 Å °-0.088 Å °0.2711 Å °0.0001 Å °
Refinement TLS groupSelection details: { A|* }

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