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- PDB-7rpz: KRAS G12D in complex with MRTX-1133 -

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Basic information

Entry
Database: PDB / ID: 7rpz
TitleKRAS G12D in complex with MRTX-1133
ComponentsIsoform 2B of GTPase KRas
KeywordsHydrolase/Hydrolase Inhibitor / Oncoprotein / G12D / GDP / GTPase / KRAS4B / Hydrolase-Hydrolase Inhibitor complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta / Chem-6IC / GUANOSINE-5'-DIPHOSPHATE / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 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 5, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)20,4334
Polymers19,3651
Non-polymers1,0683
Water4,954275
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area850 Å2
ΔGint-19 kcal/mol
Surface area8020 Å2
Unit cell
Length a, b, c (Å)39.868, 51.757, 89.611
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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
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-6IC / 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)-5-ethynyl-6-fluoronaphthalen-2-ol / MRTX-1133


Mass: 600.633 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H31F3N6O2 / 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.: 275 / 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: 2.39 Å3/Da / Density % sol: 48.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM Sodium Citrate pH 4.2,29% PEG 8K, 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-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.3→40 Å / Num. obs: 45402 / % possible obs: 97.4 % / Redundancy: 3.3 % / Biso Wilson estimate: 11.16 Å2 / CC1/2: 0.99 / Net I/σ(I): 22.9
Reflection shellResolution: 1.3→1.32 Å / Redundancy: 2.9 % / Mean I/σ(I) obs: 7.2 / Num. unique obs: 2100 / CC1/2: 0.98 / % possible all: 91.6

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6UTO

6uto


Resolution: 1.3→36.43 Å / SU ML: 0.102 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 15.3133
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1713 2186 4.85 %
Rwork0.1489 42910 -
obs0.1499 45096 96.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 17.72 Å2
Refinement stepCycle: LAST / Resolution: 1.3→36.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1414 0 1 275 1690
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01921448
X-RAY DIFFRACTIONf_angle_d1.61791972
X-RAY DIFFRACTIONf_chiral_restr0.1029218
X-RAY DIFFRACTIONf_plane_restr0.0136244
X-RAY DIFFRACTIONf_dihedral_angle_d21.9362547
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.330.17251160.16082567X-RAY DIFFRACTION92.9
1.33-1.360.19571320.15222671X-RAY DIFFRACTION97.6
1.36-1.390.20021370.15572603X-RAY DIFFRACTION97.09
1.39-1.430.20211400.15412627X-RAY DIFFRACTION96.18
1.43-1.470.18991290.15452579X-RAY DIFFRACTION94.22
1.47-1.520.17831550.14442712X-RAY DIFFRACTION99.1
1.52-1.570.16331300.13782676X-RAY DIFFRACTION98.56
1.57-1.640.18181640.14132694X-RAY DIFFRACTION98.76
1.64-1.710.17411170.13972690X-RAY DIFFRACTION97.8
1.71-1.80.1771310.14572724X-RAY DIFFRACTION98.45
1.8-1.910.16681350.14852707X-RAY DIFFRACTION97.46
1.91-2.060.17131260.14072663X-RAY DIFFRACTION96.07
2.06-2.270.1881380.14492741X-RAY DIFFRACTION98.77
2.27-2.60.14481540.15792741X-RAY DIFFRACTION98.44
2.6-3.270.19381480.16262767X-RAY DIFFRACTION97.65
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)
11.948138264520.110616902984-0.499284705981.33218485786-0.1811596200051.31504575834-0.0643249857868-0.0168311455479-0.0808288909380.02036755975680.04004050800150.04559236667330.172784758961-0.03582862666120.03864533003840.115468972074-0.006399894636510.01134669453830.0671129993231-0.003348393339220.0738814458397-0.701836960605-7.30008569891-13.7249424604
21.166925133120.00862233108989-0.712238990040.97284636641-0.1765420572391.67952157324-0.133470163224-0.0686534703282-0.2009177658310.01512205393910.0581663357749-0.06598519647950.1787044269680.01322109568710.1012429621750.1398392380360.001286416078560.02534683914460.08941071777830.002540459325020.114415886247-1.56111090932-12.3115639209-13.8870657493
31.95606583859-0.0594720161173-0.02851725614251.76341444354-0.3910437738192.01537586146-0.1181527095790.3512224824140.0135773899037-0.575823561170.06150752879230.06145925525090.299632243633-0.299600581666-0.03322505277540.250882233014-0.0359683830651-0.009880182244610.1696050120670.00191520461050.0997955838818-3.38177816940.283096559433-27.5219440932
41.54561094166-0.167019786195-0.1679757445781.33058551411-0.2648395645341.79918968386-0.006116142203930.03541322420550.114685543721-0.05426651251140.0572026250013-0.0209540219054-0.162764770957-0.0396660090618-0.04371259680120.09055406237780.008233326902810.01949163525310.055573729209-0.0006746644817570.0814720357987-1.290138549596.55229303448-15.2623235649
51.00510999220.679522606417-0.7902499834861.388756099960.6429689076772.74258578782-0.1129231638350.1367396480050.442284530394-0.1200492372290.05879366697330.225967543383-0.322748102548-0.379529159340.03466289553140.1139382509260.0134260552634-0.01122881968130.1161427046920.03053349108470.157695960821-8.580109788614.53697510109-12.6125978664
61.8695860402-0.129828461563-0.1055205196220.9136985223410.03459069291581.093301901470.0127606474457-0.2130566664660.09803691140690.06130832905820.0232294505627-0.0299970240369-0.04400394681370.0263369894127-0.02814473455950.07720410085820.01037381167550.01028888899950.0998822920811-0.006117112040860.0642979722248-3.102821727421.16048026015-4.39216873974
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 25 )
2X-RAY DIFFRACTION2chain 'A' and (resid 26 through 57 )
3X-RAY DIFFRACTION3chain 'A' and (resid 58 through 74 )
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 104 )
5X-RAY DIFFRACTION5chain 'A' and (resid 105 through 116 )
6X-RAY DIFFRACTION6chain 'A' and (resid 117 through 169 )

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