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- PDB-6p8x: Crystal structure of human KRAS G12C covalently bound to an acryl... -

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Basic information

Entry
Database: PDB / ID: 6p8x
TitleCrystal structure of human KRAS G12C covalently bound to an acryloylazetidine acetamide inhibitor.
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN/Inhibitor / Inhibitor / GTPase / SIGNALING PROTEIN / SIGNALING PROTEIN-Inhibitor complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / 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 / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / 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 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / 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 / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / 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 / Signaling by RAF1 mutants / GDP binding / 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 / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / 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 / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-O5V / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsMohr, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery ofN-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C.
Authors: Shin, Y. / Jeong, J.W. / Wurz, R.P. / Achanta, P. / Arvedson, T. / Bartberger, M.D. / Campuzano, I.D.G. / Fucini, R. / Hansen, S.K. / Ingersoll, J. / Iwig, J.S. / Lipford, J.R. / Ma, V. / ...Authors: Shin, Y. / Jeong, J.W. / Wurz, R.P. / Achanta, P. / Arvedson, T. / Bartberger, M.D. / Campuzano, I.D.G. / Fucini, R. / Hansen, S.K. / Ingersoll, J. / Iwig, J.S. / Lipford, J.R. / Ma, V. / Kopecky, D.J. / McCarter, J. / San Miguel, T. / Mohr, C. / Sabet, S. / Saiki, A.Y. / Sawayama, A. / Sethofer, S. / Tegley, C.M. / Volak, L.P. / Yang, K. / Lanman, B.A. / Erlanson, D.A. / Cee, V.J.
History
DepositionJun 8, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,37822
Polymers84,1544
Non-polymers4,22318
Water3,477193
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1146
Polymers21,0391
Non-polymers1,0765
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1146
Polymers21,0391
Non-polymers1,0765
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0745
Polymers21,0391
Non-polymers1,0364
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0745
Polymers21,0391
Non-polymers1,0364
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.327, 66.150, 78.629
Angle α, β, γ (deg.)66.48, 78.75, 89.47
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A2 - 167
2010B2 - 167
1020A2 - 166
2020C2 - 166
1030A2 - 166
2030D2 - 166
1040B2 - 166
2040C2 - 166
1050B2 - 166
2050D2 - 166
1060C1 - 167
2060D1 - 167

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 21038.613 Da / Num. of mol.: 4 / Mutation: C51S,C80L,C118S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Variant: VAR_006839 G12C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: Ca
#3: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical
ChemComp-O5V / 2-[4-bromo-2-(3-phenyl-2,5-dihydro-1H-pyrrole-1-carbonyl)phenoxy]-N-(1-propanoylazetidin-3-yl)acetamide


Mass: 512.396 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H26BrN3O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 2.01 Å3/Da / Density % sol: 38.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2M Calcium chloride, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 12, 2016
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 34585 / % possible obs: 97.5 % / Redundancy: 3.4 % / Rpim(I) all: 0.095 / Rrim(I) all: 0.18 / Rsym value: 0.152 / Χ2: 1 / Net I/σ(I): 3.9
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 1.86 / Num. unique obs: 3225 / CC1/2: 0.862 / Rpim(I) all: 0.343 / Rrim(I) all: 0.637 / Rsym value: 0.533 / Χ2: 1 / % possible all: 93.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
BOSv3data collection
DENZOv2.3.9data reduction
HKL-2000v717data reduction
SCALEPACKv2.3.9data scaling
HKL-2000v717data scaling
Cootv0.7.2model building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.11→29.86 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.919 / SU B: 7.925 / SU ML: 0.205 / Cross valid method: THROUGHOUT / ESU R: 0.46 / ESU R Free: 0.287 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31292 1594 4.7 %RANDOM
Rwork0.26529 ---
obs0.26758 32118 96.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 32.236 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20.02 Å20.03 Å2
2--0.09 Å20 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.11→29.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5328 0 254 193 5775
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0195745
X-RAY DIFFRACTIONr_bond_other_d0.0070.025221
X-RAY DIFFRACTIONr_angle_refined_deg1.4812.0127703
X-RAY DIFFRACTIONr_angle_other_deg1.433.00112011
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1875664
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.56324.432273
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.74115992
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1781540
X-RAY DIFFRACTIONr_chiral_restr0.0790.2847
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026315
X-RAY DIFFRACTIONr_gen_planes_other0.0070.021249
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_it1.7973.0832700
X-RAY DIFFRACTIONr_mcbond_other1.7863.0862691
X-RAY DIFFRACTIONr_mcangle_it2.7624.6223321
X-RAY DIFFRACTIONr_mcangle_other2.7614.6233322
X-RAY DIFFRACTIONr_scbond_it1.9373.393045
X-RAY DIFFRACTIONr_scbond_other1.9283.3953001
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.0355.0024313
X-RAY DIFFRACTIONr_long_range_B_refined4.88224.9396287
X-RAY DIFFRACTIONr_long_range_B_other4.85224.8426219
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)
11A100080.11
12B100080.11
21A96760.13
22C96760.13
31A97180.13
32D97180.13
41B96060.13
42C96060.13
51B96250.13
52D96250.13
61C102330.08
62D102330.08
LS refinement shellResolution: 2.106→2.16 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.413 115 -
Rwork0.373 1989 -
obs--83.03 %

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