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- PDB-7rt3: Crystal Structure of KRAS G12D with compound 24 (4-(4-[(1R,5S)-3,... -

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Entry
Database: PDB / ID: 7rt3
TitleCrystal Structure of KRAS G12D with compound 24 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2S,4S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE/INHIBITOR / Oncoprotein / G12D / GTPase / KRAS / Oncology / KRAS4B / MRTX-1133 / HYDROLASE-INHIBITOR complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / Chem-7NZ / GUANOSINE-5'-DIPHOSPHATE / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 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
Revision 1.3Mar 6, 2024Group: Structure summary / Category: audit_author / Item: _audit_author.name

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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)20,3914
Polymers19,3651
Non-polymers1,0263
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-20 kcal/mol
Surface area7840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.290, 53.257, 88.889
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-7NZ / 4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2S,4S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol


Mass: 558.622 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H32F2N6O2 / Feature type: SUBJECT OF INVESTIGATION
#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.: 269 / 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: 2.46 Å3/Da / Density % sol: 50.05 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 28% PEG8000, 100 mM sodium citrate, pH 4.6, 100 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: Jun 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.56→50 Å / Num. obs: 28074 / % possible obs: 99.7 % / Redundancy: 3.2 % / CC1/2: 0.99 / Net I/σ(I): 16.1
Reflection shellResolution: 1.56→1.58 Å / Mean I/σ(I) obs: 3.6 / Num. unique obs: 1277 / CC1/2: 0.97

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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: 1.56→32.13 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 19.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1988 1366 4.87 %
Rwork0.1642 26708 -
obs0.1659 28074 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 72.97 Å2 / Biso mean: 21.5202 Å2 / Biso min: 7.89 Å2
Refinement stepCycle: final / Resolution: 1.56→32.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1330 0 70 269 1669
Biso mean--14.23 34.27 -
Num. residues----168
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.56-1.610.2331290.17722573270297
1.61-1.680.20441250.166126382763100
1.68-1.750.22211330.174526372770100
1.75-1.840.2811160.169326512767100
1.84-1.960.20721220.15926642786100
1.96-2.110.19121210.160326772798100
2.11-2.320.19231540.156726542808100
2.32-2.660.2121430.171926922835100
2.66-3.350.21781510.167227182869100
3.35-32.130.16921720.159828042976100
Refinement TLS params.Method: refined / Origin x: -2.0254 Å / Origin y: -2.2137 Å / Origin z: -12.9465 Å
111213212223313233
T0.0906 Å20.0066 Å20.0071 Å2-0.0899 Å20.0056 Å2--0.0869 Å2
L0.9161 °20.2784 °2-0.0999 °2-0.9704 °2-0.1978 °2--0.8782 °2
S-0.0178 Å °-0.0484 Å °0.0339 Å °-0.0211 Å °0.039 Å °-0.0143 Å °0.0271 Å °-0.0076 Å °0.0206 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA2 - 169
2X-RAY DIFFRACTION1allA201 - 202
3X-RAY DIFFRACTION1allS1 - 270

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