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- PDB-9gh0: Human KRas4A (GMPPNP) in complex with compound 32 -

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Basic information

Entry
Database: PDB / ID: 9gh0
TitleHuman KRas4A (GMPPNP) in complex with compound 32
ComponentsGTPase KRas
KeywordsCELL CYCLE / RAS / GTPase / inhibitor
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / 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 / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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 CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
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
: / : / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 Å
AuthorsSchuettelkopf, A.W.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
CitationJournal: J.Med.Chem. / Year: 2025
Title: Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras.
Authors: Parry, C.W. / Pellicano, F. / Schuttelkopf, A.W. / Beyer, K.S. / Bower, J. / Bryson, A. / Cameron, K. / Cerutti, N.M. / Clark, J.P. / Davidson, S.C. / Davies, K. / Drysdale, M.J. / Engelman, ...Authors: Parry, C.W. / Pellicano, F. / Schuttelkopf, A.W. / Beyer, K.S. / Bower, J. / Bryson, A. / Cameron, K. / Cerutti, N.M. / Clark, J.P. / Davidson, S.C. / Davies, K. / Drysdale, M.J. / Engelman, J. / Estevan-Barber, A. / Gohlke, A. / Gray, C.H. / Guthy, D.A. / Hong, M. / Hopkins, A. / Hutchinson, L.D. / Konczal, J. / Maira, M. / McArthur, D. / Mezna, M. / McKinnon, H. / Nepravishta, R. / Ostermann, N. / Pasquali, C.C. / Pollock, K. / Pugliese, A. / Rooney, N. / Schmiedeberg, N. / Shaw, P. / Velez-Vega, C. / West, C. / West, R. / Zecri, F. / Taylor, J.B.
History
DepositionAug 14, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release
Revision 1.1May 21, 2025Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,9066
Polymers19,6071
Non-polymers1,2995
Water1,11762
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1850 Å2
ΔGint-31 kcal/mol
Surface area8280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.037, 34.230, 69.527
Angle α, β, γ (deg.)90.000, 109.710, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19607.078 Da / Num. of mol.: 1 / Mutation: C118S
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, small monomeric GTPase

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Non-polymers , 5 types, 67 molecules

#2: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CO / COBALT (II) ION


Mass: 58.933 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Co
#5: Chemical ChemComp-A1IMA / (3Z)-18-(4-aminocyclohexyl)-7-chloro-10-hydroxy-2,2-dioxo-21-piperazin-1-yl-2-lambda-6,5-dithia-3,12,18,22-tetrazatetracyclo[18.3.1.04,12.06,11]tetracosa-1(23),3,6,8,10,20(24),21-heptaen-19-one


Mass: 634.213 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H36ClN7O4S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 62 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationN

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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: 2.06 Å3/Da / Density % sol: 40.23 % / Mosaicity: 0.22 °
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 24% PEG 3350, 100 mM MgCl2, 10 mM CoCl2, 100 mM HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.57→28.92 Å / Num. obs: 22125 / % possible obs: 98.6 % / Redundancy: 3.3 % / CC1/2: 1 / Rmerge(I) obs: 0.028 / Rpim(I) all: 0.018 / Rrim(I) all: 0.033 / Net I/σ(I): 20.3 / Num. measured all: 73005
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.57-1.612.60.51514580.9230.3610.63388
7.03-28.923.10.01526210.010.01895.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.57→28.92 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.954 / SU B: 9.804 / SU ML: 0.131 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.104 / ESU R Free: 0.101 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2403 1068 4.8 %RANDOM
Rwork0.2127 ---
obs0.214 20987 98.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 86.3 Å2 / Biso mean: 41.479 Å2 / Biso min: 24.53 Å2
Baniso -1Baniso -2Baniso -3
1--0.55 Å20 Å20.94 Å2
2--2.92 Å20 Å2
3----2.42 Å2
Refinement stepCycle: final / Resolution: 1.57→28.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1293 0 77 62 1432
Biso mean--44.63 45.94 -
Num. residues----161
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0131381
X-RAY DIFFRACTIONr_bond_other_d0.0350.0181270
X-RAY DIFFRACTIONr_angle_refined_deg1.6831.7111873
X-RAY DIFFRACTIONr_angle_other_deg2.3391.6442941
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.2265158
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.27621.86775
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.15515238
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0641511
X-RAY DIFFRACTIONr_chiral_restr0.1270.2181
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021501
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02284
X-RAY DIFFRACTIONr_mcbond_it1.5822.494641
X-RAY DIFFRACTIONr_mcbond_other1.5712.489640
X-RAY DIFFRACTIONr_mcangle_it2.3893.714796
LS refinement shellResolution: 1.573→1.614 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 63 -
Rwork0.378 1405 -
all-1468 -
obs--89.35 %
Refinement TLS params.Method: refined / Origin x: 29.017 Å / Origin y: -0.477 Å / Origin z: 15.411 Å
111213212223313233
T0.0356 Å20.0059 Å20.0437 Å2-0.0475 Å20.0181 Å2--0.0707 Å2
L3.3807 °20.0111 °2-0.3819 °2-1.9584 °20.0555 °2--3.2551 °2
S0.0235 Å °-0.2764 Å °-0.156 Å °0.0232 Å °0.0093 Å °0.0745 Å °-0.1418 Å °-0.0675 Å °-0.0328 Å °

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