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- PDB-6pgo: Crystal structure of human KRAS G12C covalently bound to a phthal... -

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Basic information

Entry
Database: PDB / ID: 6pgo
TitleCrystal structure of human KRAS G12C covalently bound to a phthalazine 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-OJ1 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsMohr, C.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors.
Authors: Lanman, B.A. / Allen, J.R. / Allen, J.G. / Amegadzie, A.K. / Ashton, K.S. / Booker, S.K. / Chen, J.J. / Chen, N. / Frohn, M.J. / Goodman, G. / Kopecky, D.J. / Liu, L. / Lopez, P. / Low, J.D. ...Authors: Lanman, B.A. / Allen, J.R. / Allen, J.G. / Amegadzie, A.K. / Ashton, K.S. / Booker, S.K. / Chen, J.J. / Chen, N. / Frohn, M.J. / Goodman, G. / Kopecky, D.J. / Liu, L. / Lopez, P. / Low, J.D. / Ma, V. / Minatti, A.E. / Nguyen, T.T. / Nishimura, N. / Pickrell, A.J. / Reed, A.B. / Shin, Y. / Siegmund, A.C. / Tamayo, N.A. / Tegley, C.M. / Walton, M.C. / Wang, H.L. / Wurz, R.P. / Xue, M. / Yang, K.C. / Achanta, P. / Bartberger, M.D. / Canon, J. / Hollis, L.S. / McCarter, J.D. / Mohr, C. / Rex, K. / Saiki, A.Y. / San Miguel, T. / Volak, L.P. / Wang, K.H. / Whittington, D.A. / Zech, S.G. / Lipford, J.R. / Cee, V.J.
History
DepositionJun 24, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9948
Polymers42,0772
Non-polymers1,9176
Water2,936163
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,9974
Polymers21,0391
Non-polymers9583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,9974
Polymers21,0391
Non-polymers9583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)79.565, 106.329, 33.736
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A1 - 167
2010B1 - 167

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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.: 2 / 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-OJ1 / 1-{4-[7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenylphthalazin-1-yl]piperazin-1-yl}propan-1-one


Mass: 490.956 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H24ClFN4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 163 / 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: 1.85 Å3/Da / Density % sol: 33.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 0.2M ammonium acetate, 0.1M sodium citrate pH5.6, 32% PEG 400, 5mM magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Jul 13, 2016
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→30 Å / Num. obs: 38777 / % possible obs: 99 % / Redundancy: 4.7 % / Rpim(I) all: 0.055 / Rrim(I) all: 0.129 / Rsym value: 0.116 / Χ2: 1 / Net I/σ(I): 9.9
Reflection shellResolution: 1.6→1.66 Å / Redundancy: 4.1 % / Mean I/σ(I) obs: 4.05 / Num. unique obs: 3611 / CC1/2: 0.891 / Rpim(I) all: 0.187 / Rrim(I) all: 0.397 / Rsym value: 0.349 / Χ2: 0.994 / % possible all: 95.4

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Processing

Software
NameVersionClassification
DENZOv2.3.8data reduction
HKL-2000v717data reduction
SCALEPACKv2.3.9data scaling
HKL-2000v717data scaling
PHASERv2.5.6phasing
REFMAC5.8.0073refinement
Cootv0.7.2model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→30 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.944 / SU B: 2.012 / SU ML: 0.072 / Cross valid method: THROUGHOUT / ESU R: 0.117 / ESU R Free: 0.104 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23106 1844 4.8 %RANDOM
Rwork0.217 ---
obs0.21768 36512 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.105 Å2
Baniso -1Baniso -2Baniso -3
1--0.16 Å20 Å20 Å2
2--1.01 Å2-0 Å2
3----0.85 Å2
Refinement stepCycle: 1 / Resolution: 1.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2489 0 128 163 2780
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0192689
X-RAY DIFFRACTIONr_bond_other_d0.0030.022487
X-RAY DIFFRACTIONr_angle_refined_deg1.1712.0213624
X-RAY DIFFRACTIONr_angle_other_deg0.9123.0015714
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2185311
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.90124.194124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.18715474
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0561520
X-RAY DIFFRACTIONr_chiral_restr0.0610.2401
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022938
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02582
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_it0.9752.3681247
X-RAY DIFFRACTIONr_mcbond_other0.9742.3661246
X-RAY DIFFRACTIONr_mcangle_it1.7063.5321551
X-RAY DIFFRACTIONr_mcangle_other1.7053.5341552
X-RAY DIFFRACTIONr_scbond_it1.1552.6541442
X-RAY DIFFRACTIONr_scbond_other1.1572.6111395
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.8593.8412003
X-RAY DIFFRACTIONr_long_range_B_refined3.7720.463188
X-RAY DIFFRACTIONr_long_range_B_other3.69819.4933042
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 9026 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.13 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.236 117 -
Rwork0.247 2498 -
obs--94.68 %

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