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- PDB-7rt4: KRAS G12D in complex with Compound 5B (7-(8-chloronaphthalen-1-yl... -

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Basic information

Entry
Database: PDB / ID: 7rt4
TitleKRAS G12D in complex with Compound 5B (7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine)
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE/INHIBITOR / Oncoprotein / G12D / GDP / GTPase / KRAS4B / HYDROLASE-INHIBITOR complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / Chem-7IZ / GUANOSINE-5'-DIPHOSPHATE / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsGunn, R.J. / Thomas, N.C. / Xiaolun, W. / Lawson, J.D. / Marx, M.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor.
Authors: Wang, X. / Allen, S. / Blake, J.F. / Bowcut, V. / Briere, D.M. / Calinisan, A. / Dahlke, J.R. / Fell, J.B. / Fischer, J.P. / Gunn, R.J. / Hallin, J. / Laguer, J. / Lawson, J.D. / Medwid, J. ...Authors: Wang, X. / Allen, S. / Blake, J.F. / Bowcut, V. / Briere, D.M. / Calinisan, A. / Dahlke, J.R. / Fell, J.B. / Fischer, J.P. / Gunn, R.J. / Hallin, J. / Laguer, J. / Lawson, J.D. / Medwid, J. / Newhouse, B. / Nguyen, P. / O'Leary, J.M. / Olson, P. / Pajk, S. / Rahbaek, L. / Rodriguez, M. / Smith, C.R. / Tang, T.P. / Thomas, N.C. / Vanderpool, D. / Vigers, G.P. / Christensen, J.G. / Marx, M.A.
History
DepositionAug 12, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4315
Polymers19,3651
Non-polymers1,0674
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-20 kcal/mol
Surface area8110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.842, 51.693, 88.946
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 19364.730 Da / Num. of mol.: 1 / Mutation: G12D, C51S, C80L, C118S
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: P01116-2, small monomeric GTPase

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Non-polymers , 5 types, 125 molecules

#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.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-7IZ / 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidine


Mass: 507.002 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28ClFN6O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 2.36 Å3/Da / Density % sol: 47.99 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: PEG8000, sodium citrate, ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.1→44.47 Å / Num. obs: 11156 / % possible obs: 99.6 % / Redundancy: 13.7 % / CC1/2: 0.99 / Rmerge(I) obs: 0.17 / Net I/σ(I): 49.3
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 11.7 % / Rmerge(I) obs: 1.2 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 509 / CC1/2: 0.73 / % possible all: 96.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHASERphasing
PHENIX1.17_3644refinement
PDB_EXTRACT3.27data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6UTO

6uto


Resolution: 2.1→44.47 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 24.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.234 571 5.12 %
Rwork0.1758 10585 -
obs0.1789 11156 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 90.62 Å2 / Biso mean: 29.8915 Å2 / Biso min: 13.18 Å2
Refinement stepCycle: final / Resolution: 2.1→44.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1361 0 71 121 1553
Biso mean--27.17 37.27 -
Num. residues----170
LS refinement shellResolution: 2.1→2.31 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2862 136 -
Rwork0.2042 2549 -
obs--99 %

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