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

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Basic information

Entry
Database: PDB / ID: 4dso
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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / glial cell proliferation / 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 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / 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 / striated muscle cell differentiation / 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 / 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 / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / 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 / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / Ras protein signal transduction / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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 / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
BENZAMIDINE / 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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.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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)22,3065
Polymers21,5311
Non-polymers7764
Water2,684149
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)79.374, 79.374, 77.749
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11A-431-

HOH

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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 , 5 types, 153 molecules

#2: Chemical ChemComp-GSP / 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE


Mass: 539.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3S
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-BEN / BENZAMIDINE / Benzamidine


Mass: 120.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8N2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 149 / 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: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jan 14, 2009
Details: Side scattering bent cube-root I-beam single crystal; asymmetric cut 4.965 degs
RadiationMonochromator: Side scattering bent cube-root I-beam single crystal; asymmetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 1.85→30 Å / Num. obs: 14782 / % possible obs: 98.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 5.3 % / Rsym value: 0.059 / Net I/σ(I): 18.1
Reflection shellResolution: 1.85→1.99 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 7.4 / Rsym value: 0.158 / % possible all: 82.2

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.2.0019refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→25.92 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.942 / SU B: 6.887 / SU ML: 0.095 / Cross valid method: THROUGHOUT / ESU R: 0.141 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20705 781 5 %RANDOM
Rwork0.17022 ---
obs0.17211 14782 99.84 %-
all-15563 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.076 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å2-0.2 Å20 Å2
2---0.41 Å20 Å2
3---0.61 Å2
Refinement stepCycle: LAST / Resolution: 1.85→25.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1417 0 48 149 1614
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0221487
X-RAY DIFFRACTIONr_bond_other_d0.0050.02997
X-RAY DIFFRACTIONr_angle_refined_deg2.0661.9962011
X-RAY DIFFRACTIONr_angle_other_deg0.95332428
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.55179
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.38724.64871
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.61515261
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7831510
X-RAY DIFFRACTIONr_chiral_restr0.0880.2222
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021638
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02295
X-RAY DIFFRACTIONr_nbd_refined0.2270.2329
X-RAY DIFFRACTIONr_nbd_other0.2140.21121
X-RAY DIFFRACTIONr_nbtor_refined0.1780.2728
X-RAY DIFFRACTIONr_nbtor_other0.0860.2768
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2040.2134
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.1050.22
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2310.225
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3080.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4980.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.21.51178
X-RAY DIFFRACTIONr_mcbond_other0.2111.5369
X-RAY DIFFRACTIONr_mcangle_it1.35821443
X-RAY DIFFRACTIONr_scbond_it2.0843684
X-RAY DIFFRACTIONr_scangle_it2.884.5568
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.889 Å / Total num. of bins used: 25
RfactorNum. reflection% reflection
Rfree0.285 46 -
Rwork0.227 887 -
obs--99.89 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.3018-0.83990.25156.48752.25130.8736-0.1552-0.28580.2268-0.40010.2020.03-0.37110.0326-0.046800000018.59119.1794.55
24.31760.9070.67674.44170.75262.732-0.0434-0.28590.33360.2113-0.0184-0.0459-0.10160.11470.0618-0.16020.0134-0.0318-0.1241-0.0184-0.158718.6419.9230.142
33.83090.5691.11521.8630.39020.9806-0.0781-0.26590.32230.0436-0.09570.1188-0.08670.04560.17380.08460.0409-0.0254-0.0692-0.01790.006715.2196.247-0.587
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A448 - 449
2X-RAY DIFFRACTION2A1 - 180
3X-RAY DIFFRACTION2A201
4X-RAY DIFFRACTION2A203
5X-RAY DIFFRACTION2A204
6X-RAY DIFFRACTION2A301 - 422
7X-RAY DIFFRACTION3A423 - 447

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