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- PDB-8qug: KRAS-G12C in Complex with Compound 1 -

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Basic information

Entry
Database: PDB / ID: 8qug
TitleKRAS-G12C in Complex with Compound 1
ComponentsGTPase KRas
KeywordsTRANSFERASE / KRAS / GTPase / cancer
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / LRR domain binding / response to isolation stress / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells ...response to mineralocorticoid / GMP binding / LRR domain binding / response to isolation stress / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / 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 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / positive regulation of Ras protein signal transduction / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / liver development / GRB2 events in ERBB2 signaling / Downstream signal transduction / response to glucocorticoid / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / RAF activation / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / Signaling by RAF1 mutants / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Negative regulation of MAPK pathway / RAS processing / Regulation of RAS by GAPs / positive regulation of cellular senescence / Signaling by BRAF and RAF1 fusions / GDP binding / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / RAF/MAP kinase cascade / G protein activity / Ca2+ pathway / Ras protein signal transduction / mitochondrial outer membrane / Golgi membrane / focal adhesion / positive regulation of gene expression / positive regulation of cell population proliferation / GTPase activity / endoplasmic reticulum membrane / GTP binding / protein-containing complex binding
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 nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-WYU / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsFischer, G. / Kratochvil, B.
Funding support Austria, 1items
OrganizationGrant numberCountry
Other privateBoehringer Ingelheim RCV Austria
Citation
Journal: Science / Year: 2024
Title: Targeting cancer with small-molecule pan-KRAS degraders.
Authors: Johannes Popow / William Farnaby / Andreas Gollner / Christiane Kofink / Gerhard Fischer / Melanie Wurm / David Zollman / Andre Wijaya / Nikolai Mischerikow / Carina Hasenoehrl / Polina ...Authors: Johannes Popow / William Farnaby / Andreas Gollner / Christiane Kofink / Gerhard Fischer / Melanie Wurm / David Zollman / Andre Wijaya / Nikolai Mischerikow / Carina Hasenoehrl / Polina Prokofeva / Heribert Arnhof / Silvia Arce-Solano / Sammy Bell / Georg Boeck / Emelyne Diers / Aileen B Frost / Jake Goodwin-Tindall / Jale Karolyi-Oezguer / Shakil Khan / Theresa Klawatsch / Manfred Koegl / Roland Kousek / Barbara Kratochvil / Katrin Kropatsch / Arnel A Lauber / Ross McLennan / Sabine Olt / Daniel Peter / Oliver Petermann / Vanessa Roessler / Peggy Stolt-Bergner / Patrick Strack / Eva Strauss / Nicole Trainor / Vesna Vetma / Claire Whitworth / Siying Zhong / Jens Quant / Harald Weinstabl / Bernhard Kuster / Peter Ettmayer / Alessio Ciulli /
Abstract: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond ...Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.
#1: Journal: Biorxiv / Year: 2023
Title: Targeting cancer with small molecule pan-KRAS degraders
Authors: Popow, J. / Farnaby, W. / Gollner, A. / Kofink, C. / Fischer, G. / Wurm, M. / Zollman, D. / Wijaya, A. / Mischerikow, N. / Hasenoehrl, C. / Prokofeva, P. / Arnhof, H. / Arce-Solano, S. / ...Authors: Popow, J. / Farnaby, W. / Gollner, A. / Kofink, C. / Fischer, G. / Wurm, M. / Zollman, D. / Wijaya, A. / Mischerikow, N. / Hasenoehrl, C. / Prokofeva, P. / Arnhof, H. / Arce-Solano, S. / Bell, S. / Boeck, G. / Diers, E. / Frost, A. / Goodwin-Tindall, J. / Karolyi-Oezguer, J. / Khan, S. / Klawatsch, T. / Koegl, M. / Kousek, R. / Kratochvil, B. / Kropatsch, K. / Lauber, A. / McLennan, R. / Olt, S. / Peter, D. / Petermann, O. / Roessler, V. / Stolt-Bergner, P. / Strack, P. / Strauss, E. / Trainor, N. / Vetma, V. / Whitworth, C. / Zhong, S. / Quant, J. / Weinstabl, H. / Kuster, B. / Ettmayer, P. / Ciulli, A.
History
DepositionOct 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2024Group: Database references / Category: citation / citation_author
Revision 1.2Oct 2, 2024Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3015
Polymers19,3591
Non-polymers9424
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-27 kcal/mol
Surface area8180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.021, 91.021, 52.737
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-379-

HOH

21A-461-

HOH

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Components

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


Mass: 19358.836 Da / Num. of mol.: 1
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, small monomeric GTPase
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-WYU / (4S)-2-azanyl-4-methyl-4-[3-[2-[(2S)-2-methyl-1,4-diazepan-1-yl]pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl]-6,7-dihydro-5H-1-benzothiophene-3-carbonitrile


Mass: 450.560 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N8OS / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / 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: 2.82 Å3/Da / Density % sol: 56.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 25% PEG3350, 0.1 M BisTris, 0.27M NH4Ac

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.972422 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jan 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972422 Å / Relative weight: 1
ReflectionResolution: 1.56→64.3616 Å / Num. obs: 26183 / % possible obs: 81.9 % / Redundancy: 12.6 % / Biso Wilson estimate: 33.68 Å2 / Rmerge(I) obs: 0.041 / Rsym value: 0.041 / Net I/σ(I): 26.2
Reflection shellResolution: 1.562→1.654 Å / Redundancy: 11.8 % / Rmerge(I) obs: 1.622 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 619 / Rsym value: 1.622 / % possible all: 26.4

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDSdata reduction
XDSdata reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
BUSTER2.11.7refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.56→40 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.945 / SU R Cruickshank DPI: 0.092 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.1 / SU Rfree Blow DPI: 0.098 / SU Rfree Cruickshank DPI: 0.092
RfactorNum. reflection% reflectionSelection details
Rfree0.222 1258 4.81 %RANDOM
Rwork0.191 ---
obs0.193 26177 81.8 %-
Displacement parametersBiso mean: 37.31 Å2
Baniso -1Baniso -2Baniso -3
1-0.0997 Å20 Å20 Å2
2--0.0997 Å20 Å2
3----0.1993 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.56→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1357 0 62 204 1623
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011460HARMONIC2
X-RAY DIFFRACTIONt_angle_deg11983HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d536SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes262HARMONIC5
X-RAY DIFFRACTIONt_it1460HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion15.99
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion191SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1815SEMIHARMONIC4
LS refinement shellResolution: 1.56→1.63 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2091 -5.93 %
Rwork0.2488 619 -
all0.2465 658 -
obs--18.41 %
Refinement TLS params.Method: refined / Origin x: 90.9007 Å / Origin y: 70.5006 Å / Origin z: 56.6026 Å
111213212223313233
T0 Å20 Å20 Å2-0 Å20 Å2--0 Å2
L0 °20 °20 °2-0 °20 °2--0 °2
S0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °
Refinement TLS groupSelection details: { A|* }

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