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- PDB-8jgd: GDP-bound KRAS G12C in complex with YK-8S -

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Basic information

Entry
Database: PDB / ID: 8jgd
TitleGDP-bound KRAS G12C in complex with YK-8S
ComponentsGTPase KRas
KeywordsHYDROLASE / HYDROLASE/INHIBITOR
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / 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 / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / 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 / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / response to glucocorticoid / 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 / liver development / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Negative regulation of MAPK pathway / 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 / GDP binding / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
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
Chem-DWI / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.60037058083 Å
AuthorsZhang, Z.M. / Wang, R.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles.
Authors: Yu, Z. / He, X. / Wang, R. / Xu, X. / Zhang, Z. / Ding, K. / Zhang, Z.M. / Tan, Y. / Li, Z.
History
DepositionMay 20, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)20,5664
Polymers19,4681
Non-polymers1,0983
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-20 kcal/mol
Surface area7940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.284, 82.284, 97.479
Angle α, β, γ (deg.)90.0, 90.0, 120.0
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6

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Components

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


Mass: 19468.053 Da / Num. of mol.: 1 / Mutation: G12C
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 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-DWI / (2~{S})-1-[4-[7-(8-ethynyl-7-fluoranyl-naphthalen-1-yl)-8-fluoranyl-2-[[(2~{R},8~{S})-2-fluoranyl-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]piperazin-1-yl]-2-oxidanyl-propan-1-one


Mass: 630.659 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H33F3N6O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.45 Å3/Da / Density % sol: 49.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 200mM calcium acetate,100mM MES(PH 5.5-6.5),PEG 8000 16%-24%

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CAMD / Beamline: GCPCC / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Apr 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.6→41.142 Å / Num. obs: 26269 / % possible obs: 100 % / Redundancy: 28.6 % / Biso Wilson estimate: 15.6 Å2 / CC1/2: 0.968 / Net I/σ(I): 40.4
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 26269 / CC1/2: 0.98

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.60037058083→41.142 Å / SU ML: 0.120032597775 / Cross valid method: FREE R-VALUE / σ(F): 1.36395520505 / Phase error: 18.9292990752
RfactorNum. reflection% reflection
Rfree0.201474771249 1997 7.60935832952 %
Rwork0.168275647955 24247 -
obs0.170771429201 26244 99.741562785 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.9025173472 Å2
Refinement stepCycle: LAST / Resolution: 1.60037058083→41.142 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1353 0 75 259 1687
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007090661160331458
X-RAY DIFFRACTIONf_angle_d1.213488802451978
X-RAY DIFFRACTIONf_chiral_restr0.0458495554374218
X-RAY DIFFRACTIONf_plane_restr0.00511201977096244
X-RAY DIFFRACTIONf_dihedral_angle_d17.6535281065546
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6004-1.64040.2361922914541390.1895200504351691X-RAY DIFFRACTION99.9453850355
1.6404-1.68470.2029072294551400.1720377838331691X-RAY DIFFRACTION99.9454148472
1.6847-1.73430.2060372783651400.1677082116931702X-RAY DIFFRACTION100
1.7343-1.79030.194323805771410.169012826851708X-RAY DIFFRACTION100
1.7903-1.85430.2009396634781400.1711655317081701X-RAY DIFFRACTION100
1.8543-1.92850.2158126423811410.1738519312311717X-RAY DIFFRACTION100
1.9285-2.01630.2261398952211420.1697638407221711X-RAY DIFFRACTION100
2.0163-2.12260.175417178711410.1664843280771719X-RAY DIFFRACTION100
2.1226-2.25560.1941623416381410.1678022992341715X-RAY DIFFRACTION100
2.2556-2.42970.212514408491450.1717431306361747X-RAY DIFFRACTION100
2.4297-2.67420.1997076839141430.1719943184471731X-RAY DIFFRACTION100
2.6742-3.0610.2082844045551450.1722751988861760X-RAY DIFFRACTION99.7382198953
3.061-3.85610.2093535792241470.1583496795931787X-RAY DIFFRACTION99.588053553
3.8561-41.1420.1845113555471520.1666628971471867X-RAY DIFFRACTION97.4891356832
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)
11.28751926043-0.1270925425930.3528920170362.68660989747-0.3462444799261.54930094366-0.1323153257510.1263449351990.00197226947908-0.2075494002460.1744132745670.2571628437890.119709781929-0.16352453378-0.03538850026350.112753814357-0.0465351909664-0.01455253601020.1075221136480.01238338420750.127354172318-5.1280970351924.66215462931.78988732994
27.12080931251-4.4966830622-3.776742460864.879338032513.15054552372.398338547440.1680358497850.878936996557-0.203803843963-0.564128961527-0.09423581609050.437886443790.225508410167-0.450132418765-0.06029946315070.324961415875-0.0670501811057-0.1276168421180.2914704684050.04426943922060.251572287814-10.064145735327.2708408527-7.8074929388
31.81919693530.6969165525040.2629620417213.214085788110.5728058106531.260609358420.00259922689462-0.07773919159520.1681111020630.06996065037850.05927299392090.3488391068990.0903651400292-0.0956650863025-0.06555745399930.102780468673-0.0261971323090.002335846834860.1305690600470.02047559333050.16512692786-9.2655985388425.71482141468.18896423606
42.781500131730.212724078488-1.648442125642.782113635280.3042615938972.897098518270.0113663162051-0.05479527530430.3093687711150.03074414737290.05495138980160.115279825171-0.03063004475440.000855400176707-0.05475177854860.0693093275595-0.0228419583829-0.009962051047370.0793200988954-0.007146611453110.1279613622640.82879742601436.00653752087.30206957589
51.60606593788-0.154125583930.3063073989671.407591565710.7955242133872.75314870803-0.03150395476640.3271661218350.095811880643-0.2614814002810.0686015037411-0.110375903540.03522768582810.131933275743-0.03596409182830.156497948224-0.04154515253390.02302212848650.1367165585580.01461510173580.09912095909399.4031992598231.6716988842-1.99864262094
63.10956969032-0.3424516763360.1404913573332.2039333759-2.24238527352.29575535262-0.011385538463-0.129550253888-0.0894764449403-0.08043138610840.01953604444070.002128945320950.2936878543890.0408522322261-0.02100336187390.103416916901-0.006547244279510.001279959930510.09611999888540.001491441947880.1204448021793.4730645065920.831710079310.8812575244
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 25 )
2X-RAY DIFFRACTION2chain 'A' and (resid 26 through 37 )
3X-RAY DIFFRACTION3chain 'A' and (resid 38 through 74 )
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 116 )
5X-RAY DIFFRACTION5chain 'A' and (resid 117 through 151 )
6X-RAY DIFFRACTION6chain 'A' and (resid 152 through 169 )

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