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

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Basic information

Entry
Database: PDB / ID: 24ht
TitleHuman KRAS G12D (GDP-bound) in complex with macrocyclic peptide inhibitor AP2527
Components
  • AP2527
  • 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 / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / myoblast proliferation / 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 / positive regulation of glial cell proliferation / skeletal muscle cell differentiation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / cardiac muscle cell proliferation / SHC1 events in ERBB4 signaling / Signalling to RAS / 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 / glial cell proliferation / 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 / 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 / Signaling by FGFR3 in disease / striated muscle cell differentiation / FRS-mediated FGFR1 signaling / 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 / Downstream signal transduction / GRB2 events in ERBB2 signaling / homeostasis of number of cells within a tissue / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / response to glucocorticoid / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / RAF activation / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / visual learning / regulation of long-term neuronal synaptic plasticity / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / 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 / Regulation of RAS by GAPs / RAS processing / positive regulation of cellular senescence / Signaling by BRAF and RAF1 fusions / DAP12 signaling / GDP binding / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
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
ACETIC ACID / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 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

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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
I: AP2527
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,40611
Polymers21,5062
Non-polymers9009
Water1,946108
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3130 Å2
ΔGint-15 kcal/mol
Surface area8900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.476, 66.476, 86.805
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AI

#1: Protein Isoform 2B of GTPase KRas


Mass: 20150.582 Da / Num. of mol.: 1 / 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 AP2527


Mass: 1355.029 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 5 types, 117 molecules

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


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / 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.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H4O2
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 2.57 Å3/Da / Density % sol: 52.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.6
Details: 0.1M Sodium acetate trihydrate (pH 4.6), 8.0 %w/v Polyethylene glycol 4000

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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: 1.7→57.57 Å / Num. obs: 17465 / % possible obs: 94.4 % / Redundancy: 17.75 % / CC1/2: 0.999 / Rmerge(I) obs: 0.197 / Rpim(I) all: 0.0477 / Rrim(I) all: 0.2028 / Net I/σ(I): 9.09
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
1.701-1.9115.543.23241.4813565135658738730.557-0.070.83713.34010.76553.953.953.912.512.87.7753.9
1.911-1.95618.073.42511.5915777157778738730.5170.0270.81773.5220.8376.27576.27576.29.0875
1.956-1.99618.443.1541.7516118161188748740.605-0.0230.74633.24160.84497.897.497.897.497.89.2797.4
1.996-2.03718.342.52842.0616010160108738730.710.0680.60132.59940.87699.999.999.999.999.99.2799.9
2.037-2.08118.281.94612.6115957159578738730.786-0.0290.46322.00090.8181001001001001009.25100
2.081-2.12918.261.62343.0115941159418738730.845-0.0470.38661.66910.8021001001001001009.23100
2.129-2.18318.231.28393.715931159318748740.883-0.0010.30631.32020.8111001001001001009.21100
2.184-2.24318.221.05534.3615906159068738730.903-0.0280.25211.08520.841001001001001009.22100
2.243-2.30918.160.90474.7915857158578738730.929-0.0810.21640.93040.8191001001001001009.2100
2.309-2.38418.040.70125.8215751157518738730.964-0.0460.16880.72140.8281001001001001009.13100
2.384-2.4717.970.61656.3715703157038748740.958-0.0670.14860.63420.8091001001001001009.09100
2.47-2.5717.820.4967.4515559155598738730.971-00.12010.51040.8421001001001001009.03100
2.57-2.68717.620.38058.7315384153848738730.984-0.0080.09290.39180.81399.899.899.899.899.88.9399.8
2.687-2.83117.220.296710.3815034150348738730.9880.0210.07350.30570.8041001001001001008.74100
2.831-3.0116.230.207812.5714188141888748740.993-0.0740.05320.21450.7699.999.999.999.999.98.2699.9
3.01-3.24415.980.142915.1513952139528738730.997-0.0950.03670.14760.7231001001001001008.15100
3.245-3.57416.710.098118.714592145928738730.998-0.1460.02460.10110.62299.999.999.999.999.98.5399.9
3.574-4.118.940.071822.5916538165388738730.9990.1210.01680.07370.5151001001001001009.68100
4.1-5.16318.860.053124.5116484164848748741-0.010.01260.05450.4251001001001001009.67100
5.169-57.5718.150.04724.2415843158438738730.9990.2770.01150.04850.5211001001001001009.48100

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.25 Å57.57 Å
Translation3.25 Å57.57 Å

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Processing

Software
NameVersionClassification
autoPROC1.1.7data processing
XDSJan 31, 2020data reduction
STARANISO2.4.16data scaling
Aimless0.7.15data scaling
PHASER2.8.3phasing
PHENIX1.21.2_5419refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7YV1

7yv1


Resolution: 1.7→57.57 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 35.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2393 890 5.1 %
Rwork0.195 16573 -
obs0.1972 17463 73.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 133.8 Å2 / Biso mean: 30.9644 Å2 / Biso min: 12.51 Å2
Refinement stepCycle: final / Resolution: 1.7→57.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1457 0 63 108 1628
Biso mean--31.43 36.09 -
Num. residues----183
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.810.386760.3198971033
1.81-1.950.3139820.27551372145437
1.95-2.140.30032250.26833709393499
2.14-2.450.30261870.228337793966100
2.45-3.090.23791830.218437873970100
3.09-57.570.20152070.154238294036100

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