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- PDB-24hs: Human KRAS G12D (GDP-bound) in complex with macrocyclic peptide i... -

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Basic information

Entry
Database: PDB / ID: 24hs
TitleHuman KRAS G12D (GDP-bound) in complex with macrocyclic peptide inhibitor AP4959
Components
  • AP4959
  • Isoform 2B of GTPase KRas
KeywordsSIGNALING PROTEIN / KRAS / MACROCYCLIC PEPTIDE / ONCOLOGY / SIGNALING PROTEIN-INHIBITOR COMPLEX
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / negative regulation of epithelial cell differentiation / forebrain astrocyte development / LRR domain binding / epithelial tube branching involved in lung morphogenesis / regulation of synaptic transmission, GABAergic / response to isolation stress / response to gravity / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / negative regulation of epithelial cell differentiation / forebrain astrocyte development / LRR domain binding / epithelial tube branching involved in lung morphogenesis / regulation of synaptic transmission, GABAergic / response to isolation stress / response to gravity / type I pneumocyte differentiation / skeletal muscle cell differentiation / myoblast proliferation / Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / cardiac muscle cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / positive regulation of glial cell proliferation / 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 / homeostasis of number of cells within a tissue / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / positive regulation of Rac protein signal transduction / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / striated muscle cell differentiation / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / 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 / response to glucocorticoid / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / liver development / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / RAF activation / Constitutive Signaling by EGFRvIII / visual learning / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / gene expression / Signaling by RAF1 mutants / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Negative regulation of MAPK pathway / RAS processing / Regulation of RAS by GAPs / MAPK cascade / positive regulation of cellular senescence / Signaling by BRAF and RAF1 fusions / neuron apoptotic process / GDP binding
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.53 Å
AuthorsYamano, T. / Chiyoda, A. / Fukami, T.A. / Tanada, M. / Irie, M. / Torizawa, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2026
Title: Structure-Activity Relationship Analysis of Macrocyclic Peptide RAS Inhibitors: Spotlight on the Solvent-Exposed Region.
Authors: Chiyoda, A. / Matsuo, A. / Yamano, T. / Tanada, M.
History
DepositionMar 4, 2026Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 27, 2026Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2026Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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
B: Isoform 2B of GTPase KRas
C: Isoform 2B of GTPase KRas
D: Isoform 2B of GTPase KRas
E: Isoform 2B of GTPase KRas
F: Isoform 2B of GTPase KRas
G: Isoform 2B of GTPase KRas
H: Isoform 2B of GTPase KRas
I: AP4959
J: AP4959
K: AP4959
L: AP4959
M: AP4959
N: AP4959
O: AP4959
P: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,90742
Polymers172,54616
Non-polymers4,36126
Water5,368298
1
A: Isoform 2B of GTPase KRas
I: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2227
Polymers21,5682
Non-polymers6545
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
J: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2227
Polymers21,5682
Non-polymers6545
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Isoform 2B of GTPase KRas
K: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1606
Polymers21,5682
Non-polymers5924
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Isoform 2B of GTPase KRas
L: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0364
Polymers21,5682
Non-polymers4682
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: Isoform 2B of GTPase KRas
M: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0985
Polymers21,5682
Non-polymers5303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: Isoform 2B of GTPase KRas
N: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0985
Polymers21,5682
Non-polymers5303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: Isoform 2B of GTPase KRas
O: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0364
Polymers21,5682
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: Isoform 2B of GTPase KRas
P: AP4959
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0364
Polymers21,5682
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.254, 112.810, 202.783
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 / Protein/peptide , 2 types, 16 molecules ABCDEFGHIJKLMNOP

#1: Protein
Isoform 2B of GTPase KRas


Mass: 20150.582 Da / Num. of mol.: 8 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / Strain (production host): Tuner(DE3)pLacI / References: UniProt: P01116
#2: Protein/peptide
AP4959


Mass: 1417.714 Da / Num. of mol.: 8 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 324 molecules

#3: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 298 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.73 Å3/Da / Density % sol: 67.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 60.0% v/v Tacsimate / Temp details: 293

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 22, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.526→101.392 Å / Num. obs: 57707 / % possible obs: 87.4 % / Redundancy: 5.61 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.98 / CC1/2 anomalous: -0.06 / Rmerge(I) obs: 0.3112 / Rpim(I) all: 0.1452 / Rrim(I) all: 0.3444 / AbsDiff over sigma anomalous: 0.716 / Aniso diffraction limit 1: 2.887 Å / Aniso diffraction limit 2: 2.923 Å / Aniso diffraction limit 3: 2.56 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 6.46 / Num. measured all: 323803 / Observed signal threshold: 1.2 / % possible anomalous: 86.5 / % possible ellipsoidal: 87.4 / % possible ellipsoidal anomalous: 86.5 / % possible spherical: 66.9 / % possible spherical anomalous: 65.6 / Redundancy anomalous: 2.96 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
2.526-2.8295.533.10091.671595015950288528850.443-0.0081.44253.42930.7539.438.739.411.711.52.8938.7
2.829-2.9345.522.07491.781594515945288628860.551-0.0450.97712.2990.75658.358.658.345.945.72.8658.6
2.934-3.0085.131.69411.921479814798288528850.550.010.83631.89450.76972.573.272.573.272.52.6773.2
3.008-3.0734.841.20542.261395913959288528850.7280.0030.61411.35670.76591.992.391.992.391.92.5192.3
3.073-3.1385.041.27432.341453814538288628860.6640.0190.63251.42650.75198.498.798.498.798.42.6198.7
3.138-3.215.391.14122.681553715537288528850.72-0.0070.54311.2670.79199.899.999.899.999.82.7999.9
3.21-3.2875.540.83653.361597215972288528850.8040.0080.39390.92710.899.499.699.499.699.42.8799.6
3.287-3.3725.230.67183.741508115081288628860.876-0.020.3250.7480.7631001001001001002.71100
3.372-3.4934.830.51294.21393713937288528850.871-0.0430.25550.57530.77676.280.576.280.576.22.6180.5
3.493-3.6025.890.44275.411698216982288528850.938-0.0620.19960.48650.7391001001001001003.06100
3.602-3.7595.650.40065.591631316313288628860.918-0.0820.18440.44270.7927780.47780.4773.0580.4
3.759-3.9485.760.29026.811661616616288528850.951-0.080.13080.31930.73678.181.178.181.178.13.181.1
3.948-4.1316.170.21118.581781917819288628860.984-0.0690.09280.23110.71001001001001003.23100
4.131-4.3546.140.16529.91772317723288528850.989-0.1440.07270.18080.6851001001001001003.22100
4.354-4.6336.130.145210.541769017690288528850.99-0.2610.0640.1590.651001001001001003.23100
4.633-5.0026.110.13211.091762617626288628860.991-0.2120.05810.14450.6511001001001001003.22100
5.003-5.5186.070.141410.411751017510288528850.99-0.160.06230.15480.6521001001001001003.22100
5.519-6.3396.010.13310.681733717337288528850.987-0.230.05910.14580.6431001001001001003.21100
6.339-8.0415.890.105812.191700917009288628860.996-0.3050.04680.11590.5821001001001001003.19100
8.042-101.3925.360.085614.111546115461288528850.995-0.3040.03950.09470.51999.899.999.899.999.83.0799.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.25 Å101.39 Å
Translation3.25 Å101.39 Å

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Processing

Software
NameVersionClassificationNB
autoPROC1.1.7data processing
XDSJan 31, 2020data reduction
Aimless0.7.15data scaling
STARANISO2.4.16data scaling
PHASER2.8.3phasing
PHENIX1.21.2_5419refinement
PDB_EXTRACT3.28data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.53→101.39 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2897 2879 5.01 %
Rwork0.2268 54623 -
obs0.2299 57502 66.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 140.6 Å2 / Biso mean: 25.0589 Å2 / Biso min: 1.04 Å2
Refinement stepCycle: final / Resolution: 2.53→101.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11546 0 272 298 12116
Biso mean--21.34 18.34 -
Num. residues----1460
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 21

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.53-2.570.448910.365765662
2.57-2.611.086530.42491801835
2.61-2.660.6478120.32353083208
2.67-2.710.4912160.317328229810
2.71-2.770.372290.337869772618
2.77-2.830.3928580.32141083114128
2.83-2.890.3908660.32681547161340
2.89-2.960.37321150.31252293240859
2.96-3.040.34281710.28973175334682
3.04-3.130.32651860.29233767395397
3.13-3.230.3582110.28938454056100
3.23-3.350.33971870.261938744061100
3.35-3.480.29621730.2433222339583
3.48-3.640.29472140.22533806402099
3.64-3.830.3342020.21353271347384
3.83-4.070.27821630.20173269343284
4.08-4.390.2162130.175139054118100
4.39-4.830.22192110.170939534164100
4.83-5.530.27222160.191439274143100
5.53-6.970.25371990.221640214220100
6.97-101.390.2622330.19741334366100

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