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- PDB-9e5d: Discovery of an Orally Biovailable KRAS G12D Inhibitor -

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Basic information

Entry
Database: PDB / ID: 9e5d
TitleDiscovery of an Orally Biovailable KRAS G12D Inhibitor
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Inhibitor / Oncoprotein / GTPase / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.36 Å
AuthorsDeller, M.C. / Epling, L.B.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.
Authors: Ye, Q. / Shvartsbart, A. / Li, Z. / Gan, P. / Policarpo, R.L. / Qi, C. / Roach, J.J. / Zhu, W. / McCammant, M.S. / Hu, B. / Li, G. / Yin, H. / Carlsen, P. / Hoang, G. / Zhao, L. / Susick, R. ...Authors: Ye, Q. / Shvartsbart, A. / Li, Z. / Gan, P. / Policarpo, R.L. / Qi, C. / Roach, J.J. / Zhu, W. / McCammant, M.S. / Hu, B. / Li, G. / Yin, H. / Carlsen, P. / Hoang, G. / Zhao, L. / Susick, R. / Zhang, F. / Lai, C.T. / Allali Hassani, A. / Epling, L.B. / Gallion, A. / Kurzeja-Lipinski, K. / Gallagher, K. / Roman, V. / Farren, M.R. / Kong, W. / Deller, M.C. / Zhang, G. / Covington, M. / Diamond, S. / Kim, S. / Yao, W. / Sokolsky, A. / Wang, X.
History
DepositionOct 28, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5024
Polymers19,3871
Non-polymers1,1153
Water2,216123
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.04, 53.71, 88.85
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19386.848 Da / Num. of mol.: 1 / Fragment: residues 1-169 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-A1BEI / methyl 3-[(7M)-1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-4-[3-(dimethylamino)azetidin-1-yl]-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-imidazo[4,5-c]quinolin-2-yl]propanoate


Mass: 647.741 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H38FN7O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.41 Å3/Da / Density % sol: 48.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2M (NH4)3 Citrate, 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Feb 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.36→45.96 Å / Num. obs: 33993 / % possible obs: 87 % / Redundancy: 5.7 % / Biso Wilson estimate: 12.9 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.027 / Rrim(I) all: 0.069 / Net I/σ(I): 14.1
Reflection shellResolution: 1.36→1.43 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.69 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1701 / CC1/2: 0.54 / Rpim(I) all: 0.51 / Rrim(I) all: 0.86 / % possible all: 37.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.36→45.96 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.958 / SU B: 2.249 / SU ML: 0.039 / Cross valid method: FREE R-VALUE / ESU R: 0.072 / ESU R Free: 0.063
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.193 1690 4.974 %
Rwork0.1667 32286 -
all0.168 --
obs-33976 80.909 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 17.896 Å2
Baniso -1Baniso -2Baniso -3
1-1.056 Å2-0 Å20 Å2
2--0.03 Å2-0 Å2
3----1.086 Å2
Refinement stepCycle: LAST / Resolution: 1.36→45.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1350 0 49 123 1522
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0121459
X-RAY DIFFRACTIONr_bond_other_d0.0080.0161313
X-RAY DIFFRACTIONr_angle_refined_deg2.0681.8451999
X-RAY DIFFRACTIONr_angle_other_deg1.2931.7743031
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4395178
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.6139.28614
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg7.72851
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.57510237
X-RAY DIFFRACTIONr_dihedral_angle_6_deg17.1331068
X-RAY DIFFRACTIONr_chiral_restr0.1180.2225
X-RAY DIFFRACTIONr_gen_planes_refined0.0180.021709
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02325
X-RAY DIFFRACTIONr_nbd_refined0.1890.2244
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1240.21152
X-RAY DIFFRACTIONr_nbtor_refined0.1550.2707
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0640.2778
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0690.287
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2990.25
X-RAY DIFFRACTIONr_nbd_other0.0840.223
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0810.27
X-RAY DIFFRACTIONr_mcbond_it2.8770.873685
X-RAY DIFFRACTIONr_mcbond_other2.8750.873685
X-RAY DIFFRACTIONr_mcangle_it4.3161.582857
X-RAY DIFFRACTIONr_mcangle_other4.3161.581858
X-RAY DIFFRACTIONr_scbond_it4.3571.086774
X-RAY DIFFRACTIONr_scbond_other4.3541.086775
X-RAY DIFFRACTIONr_scangle_it6.3111.9141133
X-RAY DIFFRACTIONr_scangle_other6.3091.9141134
X-RAY DIFFRACTIONr_lrange_it10.2810.3981676
X-RAY DIFFRACTIONr_lrange_other10.27710.3981677
X-RAY DIFFRACTIONr_rigid_bond_restr3.70432772
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.36-1.3950.349300.336595X-RAY DIFFRACTION20.2396
1.395-1.4330.315630.2981017X-RAY DIFFRACTION36.5112
1.433-1.4750.263710.261395X-RAY DIFFRACTION50.5169
1.475-1.520.229680.2011679X-RAY DIFFRACTION62.2816
1.52-1.570.174900.171919X-RAY DIFFRACTION73.2143
1.57-1.6250.211070.1712237X-RAY DIFFRACTION88.4195
1.625-1.6860.2091220.1472378X-RAY DIFFRACTION97.012
1.686-1.7550.1731320.1332305X-RAY DIFFRACTION99.7952
1.755-1.8330.1761160.1282244X-RAY DIFFRACTION99.7886
1.833-1.9220.1691300.1332153X-RAY DIFFRACTION99.6508
1.922-2.0260.168850.1342067X-RAY DIFFRACTION99.9536
2.026-2.1490.1581060.1461942X-RAY DIFFRACTION99.7079
2.149-2.2970.218920.1511846X-RAY DIFFRACTION99.9484
2.297-2.480.1741010.1541717X-RAY DIFFRACTION99.8353
2.48-2.7160.202800.1741570X-RAY DIFFRACTION99.7582
2.716-3.0360.186850.1711447X-RAY DIFFRACTION99.8046
3.036-3.5030.197800.1741260X-RAY DIFFRACTION99.7024
3.503-4.2840.179560.1661106X-RAY DIFFRACTION99.4012
4.284-6.0320.221460.193876X-RAY DIFFRACTION99.3534
6.032-45.960.217300.236529X-RAY DIFFRACTION99.8214
Refinement TLS params.Method: refined / Origin x: -17.7286 Å / Origin y: 2.5901 Å / Origin z: -12.5041 Å
111213212223313233
T0.0055 Å20.0047 Å2-0.0046 Å2-0.0142 Å2-0.0017 Å2--0.015 Å2
L2.2159 °20.5702 °20.6235 °2-1.8815 °20.526 °2--1.7324 °2
S-0.0424 Å °-0.0311 Å °-0.0328 Å °-0.0373 Å °0.0365 Å °-0.0065 Å °-0.0254 Å °0.0866 Å °0.0059 Å °
Refinement TLS groupSelection: ALL

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