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- PDB-8un5: KRAS-G13D-GDP in complex with Cpd38 ((E)-1-((3S)-4-(7-(6-amino-4-... -

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Basic information

Entry
Database: PDB / ID: 8un5
TitleKRAS-G13D-GDP in complex with Cpd38 ((E)-1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-3-(1,2,3,4-tetrahydroisoquinolin-8-yl)prop-2-en-1-one)
ComponentsGTPase KRas
KeywordsHYDROLASE / ONCOPROTEIN/INHIBITOR / GTPase / KRAS / G13D / oncogenic / RIBOSOME / ONCOPROTEIN-INHIBITOR complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / glial cell proliferation / SHC-mediated cascade:FGFR2 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / Signaling by CSF1 (M-CSF) in myeloid cells / Regulation of RAS by GAPs / 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 / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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 nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-XQ6 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.31 Å
AuthorsUltsch, M.H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Structure-Based Design and Evaluation of Reversible KRAS G13D Inhibitors.
Authors: Nilewski, C. / Labadie, S. / Wei, B. / Malhotra, S. / Do, S. / Gazzard, L. / Liu, L. / Shao, C. / Murray, J. / Izrayelit, Y. / Gustafson, A. / Endres, N.F. / Ma, F. / Ye, X. / Zou, J. / Evangelista, M.
History
DepositionOct 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)41,12910
Polymers38,4272
Non-polymers2,7028
Water8,233457
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6576
Polymers19,2141
Non-polymers1,4435
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4724
Polymers19,2141
Non-polymers1,2593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.960, 41.620, 55.550
Angle α, β, γ (deg.)90.17, 91.35, 116.28
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 19213.549 Da / Num. of mol.: 2 / Fragment: GTPase, residues 2-168
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

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Non-polymers , 5 types, 465 molecules

#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-XQ6 / (2E)-1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(4R,7aS)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}-3-(1,2,3,4-tetrahydroisoquinolin-8-yl)prop-2-en-1-one


Mass: 791.279 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H43ClF4N8O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 457 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.1 Å3/Da / Density % sol: 41.54 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 4.5 / Details: 0.1 M Sodium acetate pH 4.5, 30% w/v PEG 5,000MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 0.97911 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97911 Å / Relative weight: 1
ReflectionResolution: 1.31→31.19 Å / Num. obs: 45350 / % possible obs: 38 % / Redundancy: 3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.041 / Net I/σ(I): 11.5
Reflection shellResolution: 1.31→1.45 Å / Rmerge(I) obs: 1.463 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 2267 / CC1/2: 0.366 / Rpim(I) all: 1.463 / Rrim(I) all: 2.069

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIXdev_3936refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TQA

4tqa


Resolution: 1.31→31.19 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.95 / Phase error: 29.79 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.212 2077 4.58 %
Rwork0.1782 --
obs0.1797 45344 60.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.31→31.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2690 0 182 457 3329
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042963
X-RAY DIFFRACTIONf_angle_d0.9884037
X-RAY DIFFRACTIONf_dihedral_angle_d23.8031093
X-RAY DIFFRACTIONf_chiral_restr0.071434
X-RAY DIFFRACTIONf_plane_restr0.004507
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.31-1.340.016710.717828X-RAY DIFFRACTION1
1.34-1.380.974490.7496148X-RAY DIFFRACTION3
1.38-1.410.7859370.5729714X-RAY DIFFRACTION15
1.41-1.460.4715630.43441354X-RAY DIFFRACTION28
1.46-1.50.37041240.36841955X-RAY DIFFRACTION41
1.5-1.560.36531430.2962420X-RAY DIFFRACTION51
1.56-1.620.2371510.28022787X-RAY DIFFRACTION59
1.62-1.690.31481510.2613102X-RAY DIFFRACTION65
1.69-1.780.27111890.22023508X-RAY DIFFRACTION74
1.78-1.890.24211490.20914217X-RAY DIFFRACTION88
1.89-2.040.23062230.18534570X-RAY DIFFRACTION95
2.04-2.240.21672230.17064567X-RAY DIFFRACTION96
2.24-2.570.21551660.16034672X-RAY DIFFRACTION97
2.57-3.230.19512020.15754652X-RAY DIFFRACTION97
3.24-31.190.15292460.13734573X-RAY DIFFRACTION97
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)
10.20820.1272-0.03370.59260.01610.80510.07690.00310.0436-0.0998-0.1727-0.18220.03490.2355-0.00120.11980.01450.0040.14980.03240.158113.471-1.8384-20.6209
20.63510.0503-0.44721.5651-0.76291.78420.0885-0.12390.00020.2003-0.1232-0.0526-0.17120.10330.00630.0907-0.02420.00380.0814-0.00770.0665.6533-4.1029-8.2221
30.801-0.2693-0.24450.8126-0.49361.22980.0787-0.08360.12560.0579-0.0536-0.0166-0.3231-0.01430.00010.15490.00620.0110.1219-0.01650.13612.97156.8251-14.1799
40.3901-0.42140.17430.4648-0.10831.2171-0.08380.0042-0.09760.08950.03390.11260.1704-0.0831-0.00240.09710.00020.00560.1087-0.00410.118710.4193-28.6635-34.1912
50.34750.0406-0.12370.1601-0.0320.51070.0410.047-0.3560.05160.0150.2464-0.0289-0.1262-00.13590.01320.02170.13610.0250.1962-1.2812-28.4216-33.9922
61.91710.1234-1.17590.08470.25742.1618-0.1720.1094-0.33330.03120.03820.15270.5983-0.0824-0.44860.1723-0.0249-0.00180.1153-0.04860.127610.4607-35.8473-49.5611
70.2598-0.2194-0.36420.94950.32180.8943-0.02820.0855-0.0894-0.1405-0.0050.0196-0.0113-0.0388-0.00020.1124-0.0199-0.00890.128-0.00490.121810.9635-21.6332-48.4115
8-0.0001-0.00320.01280.1964-0.23420.5402-0.14880.03930.04220.130.1022-0.2009-0.48040.131-0.00280.1755-0.035-0.03190.10220.00090.126915.8589-10.4956-41.5447
90.2654-0.0346-0.11730.16440.07350.1698-0.09290.06070.12630.0860.01080.0143-0.11660.05370.00010.12460.0023-0.00760.10890.00360.112810.0597-15.4213-34.6859
100.0526-0.09210.01270.5806-0.17671.2138-0.0260.0671-0.19370.00790.13060.2881-0.1996-0.42350.0240.091-0.0044-0.0210.1772-0.00160.1507-2.2076-19.2237-40.6404
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 0 through 57 )
2X-RAY DIFFRACTION2chain 'A' and (resid 58 through 126 )
3X-RAY DIFFRACTION3chain 'A' and (resid 127 through 168 )
4X-RAY DIFFRACTION4chain 'B' and (resid 1 through 37 )
5X-RAY DIFFRACTION5chain 'B' and (resid 38 through 57 )
6X-RAY DIFFRACTION6chain 'B' and (resid 58 through 74 )
7X-RAY DIFFRACTION7chain 'B' and (resid 75 through 116 )
8X-RAY DIFFRACTION8chain 'B' and (resid 117 through 137 )
9X-RAY DIFFRACTION9chain 'B' and (resid 138 through 151 )
10X-RAY DIFFRACTION10chain 'B' and (resid 152 through 168 )

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