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- PDB-4dst: Small-molecule ligands bind to a distinct pocket in Ras and inhib... -

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Entry
Database: PDB / ID: 4dst
TitleSmall-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
ComponentsGTPase KRas, isoform 2B
KeywordsHYDROLASE / Small G-protein / Signaling
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 / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / 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 / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / 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 / regulation of long-term neuronal synaptic plasticity / Constitutive Signaling by EGFRvIII / 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 nucleotide triphosphate hydrolases ...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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
2-(4,6-dichloro-2-methyl-1H-indol-3-yl)ethanamine / ACETATE ION / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsOh, A. / Maurer, T. / Garrenton, L.S. / Pitts, K. / Anderson, D.J. / Skelton, N.J. / Fauber, B.P. / Pan, B. / Malek, S. / Stokoe, D. ...Oh, A. / Maurer, T. / Garrenton, L.S. / Pitts, K. / Anderson, D.J. / Skelton, N.J. / Fauber, B.P. / Pan, B. / Malek, S. / Stokoe, D. / Ludlam, M. / Bowman, K.K. / Wu, J. / Giannetti, A.M. / Starovasnik, M.A. / Mellman, I. / Jackson, P.K. / Ruldolph, J. / Fang, G. / Wang, W.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2012
Title: Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity.
Authors: Maurer, T. / Garrenton, L.S. / Oh, A. / Pitts, K. / Anderson, D.J. / Skelton, N.J. / Fauber, B.P. / Pan, B. / Malek, S. / Stokoe, D. / Ludlam, M.J. / Bowman, K.K. / Wu, J. / Giannetti, A.M. ...Authors: Maurer, T. / Garrenton, L.S. / Oh, A. / Pitts, K. / Anderson, D.J. / Skelton, N.J. / Fauber, B.P. / Pan, B. / Malek, S. / Stokoe, D. / Ludlam, M.J. / Bowman, K.K. / Wu, J. / Giannetti, A.M. / Starovasnik, M.A. / Mellman, I. / Jackson, P.K. / Rudolph, J. / Wang, W. / Fang, G.
History
DepositionFeb 19, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 4, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 18, 2012Group: Database references
Revision 1.2Jun 6, 2012Group: Database references
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas, isoform 2B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6359
Polymers21,5311
Non-polymers1,1048
Water1,62190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.923, 78.923, 78.631
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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Protein , 1 types, 1 molecules A

#1: Protein GTPase KRas, isoform 2B / KRas 4B / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras / GTPase KRas / N-terminally processed


Mass: 21530.574 Da / Num. of mol.: 1 / Mutation: G12D
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, Hydrolases; Acting on acid anhydrides

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Non-polymers , 8 types, 98 molecules

#2: Chemical ChemComp-9LI / 2-(4,6-dichloro-2-methyl-1H-indol-3-yl)ethanamine


Mass: 243.132 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H12Cl2N2
#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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsTHE SEQUENCE MATCHES UNIPROT ENTRY P01116, ISOFORM 2B WITH IDENTIFIER P01116-2.

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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: 2.19 Å3/Da / Density % sol: 43.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.2 uL + 0.2 uL drops containing 40 mg/mL KRas, 0.1 M TrisCl, 25% polyethylene glycol 4000, 0.2 M NaOAc, 2% benzamidine-HCl, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 3, 2010
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.3→30 Å / Num. all: 7788 / Num. obs: 8242 / % possible obs: 94.5 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 5.2 % / Biso Wilson estimate: 35.7 Å2 / Rsym value: 0.092 / Net I/σ(I): 18
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 3 / Num. unique all: 832 / Rsym value: 0.332 / % possible all: 70.8

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.6.4_486)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→25.793 Å / SU ML: 0.22 / σ(F): 1.97 / Phase error: 19.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2087 393 5.09 %RANDOM
Rwork0.1592 ---
all0.162 8109 --
obs0.1617 7716 94.44 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 46.259 Å2 / ksol: 0.342 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--3.5514 Å2-0 Å20 Å2
2---3.5514 Å2-0 Å2
3---7.1029 Å2
Refinement stepCycle: LAST / Resolution: 2.3→25.793 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1417 0 67 90 1574
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051520
X-RAY DIFFRACTIONf_angle_d1.0052058
X-RAY DIFFRACTIONf_dihedral_angle_d14.818567
X-RAY DIFFRACTIONf_chiral_restr0.059227
X-RAY DIFFRACTIONf_plane_restr0.003263
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.380.24721120.16912186X-RAY DIFFRACTION84
2.6282-3.31020.20531340.1532567X-RAY DIFFRACTION100
3.3102-25.79410.20151470.15972570X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 18.7262 Å / Origin y: 9.8187 Å / Origin z: 0.2962 Å
111213212223313233
T0.1244 Å2-0.0101 Å2-0.0095 Å2-0.1504 Å2-0.0133 Å2--0.1346 Å2
L1.2115 °20.1333 °20.2607 °2-0.9535 °2-0.5664 °2--1.1451 °2
S-0.0648 Å °-0.0179 Å °0.1087 Å °0.039 Å °-0.0849 Å °-0.0407 Å °-0.0642 Å °0.123 Å °0 Å °
Refinement TLS groupSelection details: ALL

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