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- PDB-6gqy: KRAS-169 Q61H GPPNHP + CH-3 -

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Basic information

Entry
Database: PDB / ID: 6gqy
TitleKRAS-169 Q61H GPPNHP + CH-3
ComponentsGTPase KRas
KeywordsONCOPROTEIN / KRAS
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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells ...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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / skeletal muscle cell differentiation / 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 / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / 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 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / positive regulation of glial cell proliferation / 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 / homeostasis of number of cells within a tissue / 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 / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / 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 / negative regulation of neuron apoptotic process / gene expression / Ras protein signal transduction / mitochondrial outer membrane / Golgi membrane / focal adhesion / GTPase activity
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 domain 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
Chem-F8Q / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsCruz-Migoni, A. / Quevedo, C.E. / Carr, S.B. / Phillips, S.V.E. / Rabbitts, T.H.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Wellcome Trust099246/Z/12/Z United Kingdom
Bloodwise12051 United Kingdom
Medical Research Council (United Kingdom)MR/J000612/1 United Kingdom
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2019
Title: Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.
Authors: Cruz-Migoni, A. / Canning, P. / Quevedo, C.E. / Bataille, C.J.R. / Bery, N. / Miller, A. / Russell, A.J. / Phillips, S.E.V. / Carr, S.B. / Rabbitts, T.H.
History
DepositionJun 8, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 6, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim
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.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.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _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_asym_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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
C: GTPase KRas
D: GTPase KRas
E: GTPase KRas
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,91922
Polymers117,1146
Non-polymers4,80516
Water86548
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4474
Polymers19,5191
Non-polymers9283
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4474
Polymers19,5191
Non-polymers9283
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4474
Polymers19,5191
Non-polymers9283
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4474
Polymers19,5191
Non-polymers9283
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0663
Polymers19,5191
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0663
Polymers19,5191
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.531, 118.678, 156.996
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16B
26C
17B
27D
18B
28E
19B
29F
110C
210D
111C
211E
112C
212F
113D
213E
114D
214F
115E
215F

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: TYR / Beg label comp-ID: TYR / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: _ / Auth seq-ID: -3 - 167 / Label seq-ID: 1 - 171

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14AA
24EE
15AA
25FF
16BB
26CC
17BB
27DD
18BB
28EE
19BB
29FF
110CC
210DD
111CC
211EE
112CC
212FF
113DD
213EE
114DD
214FF
115EE
215FF

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

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Components

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


Mass: 19519.014 Da / Num. of mol.: 6 / Mutation: Q61H
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
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical
ChemComp-F8Q / [4-[[3-fluoranyl-2-methoxy-4-(3-methoxyphenyl)phenyl]amino]phenyl]methyl-dimethyl-azanium


Mass: 381.463 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H26FN2O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 48 / Source method: isolated from a natural source / Formula: H2O

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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: 2.49 Å3/Da / Density % sol: 50.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 8-15% w/v polyethylene glycol 3350 and 0.2M Lithium citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.75→118 Å / Num. obs: 31557 / % possible obs: 99.8 % / Redundancy: 10.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.067 / Rrim(I) all: 0.16 / Net I/σ(I): 16
Reflection shellResolution: 2.75→2.88 Å / Redundancy: 11 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 4134 / CC1/2: 0.916 / Rpim(I) all: 0.24 / Rrim(I) all: 0.59 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0218refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GFT

3gft


Resolution: 2.75→94.67 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.896 / SU B: 12.626 / SU ML: 0.245 / Cross valid method: THROUGHOUT / ESU R Free: 0.366 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24744 1561 5 %RANDOM
Rwork0.20476 ---
obs0.20682 29946 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 44.271 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å20 Å20 Å2
2--1.78 Å2-0 Å2
3----1.37 Å2
Refinement stepCycle: 1 / Resolution: 2.75→94.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7940 0 310 48 8298
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198437
X-RAY DIFFRACTIONr_bond_other_d0.0010.027654
X-RAY DIFFRACTIONr_angle_refined_deg1.5021.97311440
X-RAY DIFFRACTIONr_angle_other_deg0.7972.99117721
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.57751001
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.92824.239401
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.579151448
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9521558
X-RAY DIFFRACTIONr_chiral_restr0.0810.21272
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029267
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021723
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.7114.1724013
X-RAY DIFFRACTIONr_mcbond_other3.7114.1724012
X-RAY DIFFRACTIONr_mcangle_it6.1036.2385002
X-RAY DIFFRACTIONr_mcangle_other6.1036.2395003
X-RAY DIFFRACTIONr_scbond_it4.9354.9164424
X-RAY DIFFRACTIONr_scbond_other4.9364.9174422
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.0847.1356436
X-RAY DIFFRACTIONr_long_range_B_refined11.01348.0859069
X-RAY DIFFRACTIONr_long_range_B_other11.01248.0819070
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A52880.07
12B52880.07
21A51130.07
22C51130.07
31A51540.06
32D51540.06
41A51130.06
42E51130.06
51A51750.07
52F51750.07
61B51140.06
62C51140.06
71B51710.05
72D51710.05
81B51450.05
82E51450.05
91B52220.06
92F52220.06
101C51190.06
102D51190.06
111C50700.06
112E50700.06
121C50990.07
122F50990.07
131D51620.06
132E51620.06
141D51720.06
142F51720.06
151E51080.06
152F51080.06
LS refinement shellResolution: 2.75→2.821 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.395 114 -
Rwork0.351 2162 -
obs--99.78 %

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