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- PDB-9bhq: Crystal structure of KRAS G12A in a transition state mimetic comp... -

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Basic information

Entry
Database: PDB / ID: 9bhq
TitleCrystal structure of KRAS G12A in a transition state mimetic complex with CYPA and RMC-7977
Components
  • Isoform 2B of GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN / GTPase SIGNALING PROTEIN Isomerase
Function / homology
Function and homology information


negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / negative regulation of viral life cycle / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / endothelial cell activation ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / negative regulation of viral life cycle / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / endothelial cell activation / negative regulation of stress-activated MAPK cascade / Basigin interactions / forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / cyclosporin A binding / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / Rac protein signal transduction / Early Phase of HIV Life Cycle / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Integration of provirus / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / APOBEC3G mediated resistance to HIV-1 infection / viral release from host cell / protein peptidyl-prolyl isomerization / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / Calcineurin activates NFAT / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / Binding and entry of HIV virion / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / positive regulation of viral genome replication / SHC-mediated cascade:FGFR2 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / 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 FGFR4 in disease / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / : / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / neutrophil chemotaxis / Signaling by FGFR1 in disease / activation of protein kinase B activity / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / negative regulation of protein phosphorylation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / peptidylprolyl isomerase / positive regulation of protein secretion / peptidyl-prolyl cis-trans isomerase activity / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / negative regulation of protein kinase activity
Similarity search - Function
Cyclophilin-type peptidyl-prolyl cis-trans isomerase / Cyclophilin-type peptidyl-prolyl cis-trans isomerase, conserved site / Cyclophilin-type peptidyl-prolyl cis-trans isomerase signature. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain profile. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain / Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD / Cyclophilin-like domain superfamily / Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases ...Cyclophilin-type peptidyl-prolyl cis-trans isomerase / Cyclophilin-type peptidyl-prolyl cis-trans isomerase, conserved site / Cyclophilin-type peptidyl-prolyl cis-trans isomerase signature. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain profile. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain / Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD / Cyclophilin-like domain superfamily / 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
ALUMINUM FLUORIDE / GUANOSINE-5'-DIPHOSPHATE / : / GTPase KRas / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsPourfarjam, Y. / Goldgur, Y. / Cuevas-Navarro, A. / Lito, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: To Be Published
Title: Crystal structure of KRAS G12A in a transition state mimetic complex with CYPA and RMC-7977
Authors: Pourfarjam, Y. / Goldgur, Y. / Cuevas-Navarro, A. / Lito, P.
History
DepositionApr 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Peptidyl-prolyl cis-trans isomerase A
D: Peptidyl-prolyl cis-trans isomerase A
A: Isoform 2B of GTPase KRas
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,70612
Polymers74,8734
Non-polymers2,8338
Water6,774376
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.606, 83.312, 127.691
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules BDAC

#1: Protein Peptidyl-prolyl cis-trans isomerase A / PPIase A / Cyclophilin A / Cyclosporin A-binding protein / Rotamase A


Mass: 18093.555 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIA, CYPA / Production host: Escherichia coli (E. coli) / References: UniProt: P62937, peptidylprolyl isomerase
#2: Protein Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19342.836 Da / Num. of mol.: 2 / Mutation: G12A
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, small monomeric GTPase

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Non-polymers , 5 types, 384 molecules

#3: Chemical ChemComp-ZNI / (1R,5S,6r)-N-[(1P,7S,9S,13S,20M)-20-{5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-21-ethyl-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1~2,5~.1~9,13~.0~22,26~]octacosa-1(24),2,5(28),19,22,25-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide / RMC-7977


Mass: 865.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H60N8O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#5: Chemical ChemComp-AF3 / ALUMINUM FLUORIDE


Mass: 83.977 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: AlF3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.33 Å3/Da / Density % sol: 47.22 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / Details: 100 mM Tris pH 8.5, 15% PEG 10000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.978 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 27, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.9→29.81 Å / Num. obs: 52196 / % possible obs: 93.1 % / Redundancy: 5.4 % / Rrim(I) all: 0.155 / Net I/σ(I): 15.307
Reflection shellResolution: 1.9→1.93 Å / Num. unique obs: 2146 / Rrim(I) all: 0.813

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→29.81 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2323 2662 5.11 %
Rwork0.1923 --
obs0.1944 52117 93.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→29.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5166 0 190 376 5732
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01
X-RAY DIFFRACTIONf_angle_d0.888
X-RAY DIFFRACTIONf_dihedral_angle_d13.237767
X-RAY DIFFRACTIONf_chiral_restr0.051789
X-RAY DIFFRACTIONf_plane_restr0.007945
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.930.31991390.29862107X-RAY DIFFRACTION76
1.93-1.970.28891120.26562190X-RAY DIFFRACTION80
1.97-2.010.28811090.24822257X-RAY DIFFRACTION82
2.01-2.050.2931200.2312357X-RAY DIFFRACTION85
2.05-2.10.26681280.22442398X-RAY DIFFRACTION87
2.1-2.150.26091410.22352428X-RAY DIFFRACTION88
2.15-2.210.24781230.21742499X-RAY DIFFRACTION89
2.21-2.280.22621490.20452481X-RAY DIFFRACTION91
2.28-2.350.24641350.19932609X-RAY DIFFRACTION94
2.35-2.440.26081410.19972682X-RAY DIFFRACTION96
2.44-2.530.23781380.20272767X-RAY DIFFRACTION99
2.53-2.650.27041530.20632772X-RAY DIFFRACTION100
2.65-2.790.24111440.20842781X-RAY DIFFRACTION100
2.79-2.960.25161650.19992789X-RAY DIFFRACTION100
2.96-3.190.21151270.19652841X-RAY DIFFRACTION100
3.19-3.510.24161720.17932786X-RAY DIFFRACTION100
3.51-4.020.19681550.16392825X-RAY DIFFRACTION100
4.02-5.060.19131520.15192890X-RAY DIFFRACTION100
5.06-29.810.21491590.19012996X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -13.2662 Å / Origin y: 20.4834 Å / Origin z: -21.8223 Å
111213212223313233
T0.1574 Å20.001 Å2-0.021 Å2-0.1663 Å2-0.0159 Å2--0.1587 Å2
L0.6957 °2-0.4174 °2-0.2607 °2-0.7894 °2-0.0349 °2--0.5922 °2
S0.1489 Å °0.1288 Å °-0.0124 Å °-0.1741 Å °-0.0716 Å °0.0334 Å °0.0089 Å °-0.0234 Å °-0.0735 Å °
Refinement TLS groupSelection details: all

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