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- PDB-7rt5: Crystal structure of KRAS G12D with compound 36 (4-[(1R,5S)-3,8-d... -

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Basic information

Entry
Database: PDB / ID: 7rt5
TitleCrystal structure of KRAS G12D with compound 36 (4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(4s,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidine) bound
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE/INHIBITOR / Oncoprotein / G12D / GDP / GTPase / KRAS4B / HYDROLASE-INHIBITOR complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / Chem-7OE / GUANOSINE-5'-DIPHOSPHATE / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.29 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)20,3994
Polymers19,3651
Non-polymers1,0343
Water4,738263
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area840 Å2
ΔGint-19 kcal/mol
Surface area7930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.865, 51.935, 88.658
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#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
#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-7OE / 4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(4s,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidine


Mass: 566.644 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H32F2N6O
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 263 / 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: 2.37 Å3/Da / Density % sol: 48.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 100 mM sodium citrate, pH 4.5, 26% PEG8000, 200 mM ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.29→50 Å / Num. obs: 45349 / % possible obs: 96.6 % / Redundancy: 3.2 % / CC1/2: 0.99 / Net I/σ(I): 25.4
Reflection shellResolution: 1.29→1.31 Å / Redundancy: 2.9 % / Num. unique obs: 2096 / CC1/2: 0.94 / % possible all: 91.7

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7RPZ

7rpz


Resolution: 1.29→44.81 Å / SU ML: 0.1 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 17.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1872 2225 4.91 %
Rwork0.1625 43124 -
obs0.1637 45349 96.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 71.01 Å2 / Biso mean: 20.0976 Å2 / Biso min: 8.03 Å2
Refinement stepCycle: final / Resolution: 1.29→44.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1331 0 71 263 1665
Biso mean--13.39 31.5 -
Num. residues----169
LS refinement shellResolution: 1.29→1.32 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2487 119 -
Rwork0.1919 2523 -
obs--91 %
Refinement TLS params.Method: refined / Origin x: -1.9999 Å / Origin y: -1.0737 Å / Origin z: -12.2524 Å
111213212223313233
T0.0762 Å20.006 Å20.0048 Å2-0.0654 Å20.0023 Å2--0.0693 Å2
L1.8471 °20.1369 °2-0.5435 °2-1.235 °2-0.0348 °2--1.5935 °2
S0.0006 Å °-0.0645 Å °0.0419 Å °-0.0396 Å °0.0314 Å °-0.0016 Å °-0.0071 Å °-0.0328 Å °-0.0235 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 169
2X-RAY DIFFRACTION1allA201 - 401
3X-RAY DIFFRACTION1allS1 - 267

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