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- PDB-7rt2: Crystal Structure of KRAS G12D with compound 25 (4-(4-[(1R,5S)-3,... -

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Entry
Database: PDB / ID: 7rt2
TitleCrystal Structure of KRAS G12D with compound 25 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-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-7NL / GUANOSINE-5'-DIPHOSPHATE / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 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)20,5456
Polymers19,3651
Non-polymers1,1805
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1340 Å2
ΔGint-17 kcal/mol
Surface area7810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.960, 52.972, 90.708
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 , 6 types, 177 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-7NL / 4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-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
#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: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.54 Å3/Da / Density % sol: 51.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 28% PEG8000, 100 mM sodium citrate, pH 5.0, 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: Oct 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.59→50 Å / Num. obs: 26958 / % possible obs: 99.1 % / Redundancy: 3.2 % / CC1/2: 0.99 / Net I/σ(I): 25.2
Reflection shellResolution: 1.59→1.62 Å / Redundancy: 3.2 % / Num. unique obs: 1277 / CC1/2: 0.97 / % possible all: 97.4

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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: 1.59→45.74 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 16.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1796 1362 5.06 %
Rwork0.1569 25548 -
obs0.1581 26910 98.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 71.24 Å2 / Biso mean: 23.1632 Å2 / Biso min: 9.83 Å2
Refinement stepCycle: final / Resolution: 1.59→45.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1329 0 94 172 1595
Biso mean--21.05 36.64 -
Num. residues----169
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.59-1.650.22411400.1741248898
1.65-1.710.17991210.157255499
1.71-1.790.18671310.1509251799
1.79-1.890.1631320.141254699
1.89-20.18021270.1428251899
2-2.160.15181470.1455256899
2.16-2.370.17121350.1422255199
2.38-2.720.17461350.1544255298
2.72-3.430.17381400.1613259799
3.43-44.740.19221540.1691265797
Refinement TLS params.Method: refined / Origin x: -1.8989 Å / Origin y: -2.3526 Å / Origin z: -13.1896 Å
111213212223313233
T0.1064 Å20.0172 Å20.0245 Å2-0.0937 Å20.0042 Å2--0.1006 Å2
L1.752 °20.4134 °2-0.5608 °2-1.7373 °2-0.3012 °2--1.9846 °2
S0.0223 Å °0.021 Å °0.0729 Å °-0.0187 Å °0.0622 Å °-0.0187 Å °-0.0735 Å °-0.0847 Å °-0.0597 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 169
2X-RAY DIFFRACTION1allA201 - 501
3X-RAY DIFFRACTION1allS1 - 179

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