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- PDB-9bgh: Crystal structure of KRAS G12D in a transition state mimetic comp... -

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Basic information

Entry
Database: PDB / ID: 9bgh
TitleCrystal structure of KRAS G12D in a transition state mimetic complex with CYPA and RMC-7977
Components
  • GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN / GTPase Isomerase
Function / homology
Function and homology information


negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / protein peptidyl-prolyl isomerization / cyclosporin A binding ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / protein peptidyl-prolyl isomerization / cyclosporin A binding / negative regulation of protein phosphorylation / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / activation of protein kinase B activity / neutrophil chemotaxis / peptidyl-prolyl cis-trans isomerase activity / small monomeric GTPase / negative regulation of protein kinase activity / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / peptidylprolyl isomerase / platelet activation / cytoplasmic side of plasma membrane / platelet aggregation / positive regulation of NF-kappaB transcription factor activity / GDP binding / integrin binding / protein folding / positive regulation of protein phosphorylation / G protein activity / cellular response to oxidative stress / Ras protein signal transduction / positive regulation of MAPK cascade / apoptotic process / GTP binding / extracellular region / nucleus / cytosol / cytoplasm
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. / Rho (Ras homology) subfamily of Ras-like 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. / 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 / : / Peptidyl-prolyl cis-trans isomerase A / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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: Nature / Year: 2025
Title: Pharmacological restoration of GTP hydrolysis by mutant RAS.
Authors: Cuevas-Navarro, A. / Pourfarjam, Y. / Hu, F. / Rodriguez, D.J. / Vides, A. / Sang, B. / Fan, S. / Goldgur, Y. / de Stanchina, E. / Lito, P.
History
DepositionApr 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Database references / Source and taxonomy / Structure summary
Category: citation / entity_src_gen / struct
Item: _citation.title / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id ..._citation.title / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _struct.title
Revision 1.2Jan 29, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)77,71011
Polymers74,9614
Non-polymers2,7497
Water8,737485
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.483, 81.787, 127.832
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: P62938, peptidylprolyl isomerase
#2: Protein GTPase KRas / K-Ras 2 / Ki-Ras / K-ras


Mass: 19386.848 Da / Num. of mol.: 2 / Mutation: G12D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS / Production host: Escherichia coli (E. coli) / References: UniProt: P79800, small monomeric GTPase

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Non-polymers , 5 types, 492 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-AF3 / ALUMINUM FLUORIDE


Mass: 83.977 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: AlF3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 485 / 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: 2.28 Å3/Da / Density % sol: 46.13 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / Details: 100 mM Tris-HCl pH 8.5, 22% PEG 8K.

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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: 0.9793 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 9, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.175→34.45 Å / Num. obs: 77267 / % possible obs: 74.7 % / Redundancy: 7 % / CC1/2: 0.998 / Net I/σ(I): 5.4
Reflection shell
Resolution (Å)Num. unique obsCC1/2Diffraction-ID
1.452-1.46122320.05181
1.533-1.54523180.17361
1.582-1.59522790.18881
1.637-1.65221900.30341

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→33.48 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2509 3928 5.08 %
Rwork0.2176 --
obs0.2193 77261 92.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.65→33.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5166 0 186 485 5837
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.018
X-RAY DIFFRACTIONf_angle_d1.531
X-RAY DIFFRACTIONf_dihedral_angle_d15.749782
X-RAY DIFFRACTIONf_chiral_restr0.084789
X-RAY DIFFRACTIONf_plane_restr0.013946
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.670.46511380.39552752X-RAY DIFFRACTION98
1.67-1.690.44821600.37312714X-RAY DIFFRACTION98
1.69-1.710.36011350.34182801X-RAY DIFFRACTION100
1.71-1.740.39521470.34112734X-RAY DIFFRACTION99
1.74-1.760.33151470.30742781X-RAY DIFFRACTION100
1.76-1.790.34261270.2932807X-RAY DIFFRACTION100
1.79-1.820.31051770.27692785X-RAY DIFFRACTION100
1.82-1.850.31511840.26592719X-RAY DIFFRACTION100
1.85-1.880.32191600.24922803X-RAY DIFFRACTION100
1.88-1.90.26151050.2452071X-RAY DIFFRACTION100
1.93-1.950.2913930.25231758X-RAY DIFFRACTION99
1.95-1.990.33551420.25072797X-RAY DIFFRACTION100
1.99-2.030.29491560.25242782X-RAY DIFFRACTION100
2.03-2.050.2838600.26381254X-RAY DIFFRACTION99
2.09-2.130.29531280.2292397X-RAY DIFFRACTION99
2.13-2.190.26861400.22242791X-RAY DIFFRACTION100
2.19-2.230.25691120.22171967X-RAY DIFFRACTION100
2.26-2.330.25581410.21262706X-RAY DIFFRACTION99
2.33-2.410.22711670.22342805X-RAY DIFFRACTION100
2.41-2.510.25431440.22292824X-RAY DIFFRACTION100
2.51-2.620.27181480.22222824X-RAY DIFFRACTION100
2.62-2.760.27721390.22042847X-RAY DIFFRACTION100
2.76-2.930.22111460.20532821X-RAY DIFFRACTION100
2.93-3.160.24671510.21512840X-RAY DIFFRACTION100
3.16-3.470.21791120.20312390X-RAY DIFFRACTION83
3.48-3.980.21271360.1872631X-RAY DIFFRACTION92
3.98-5.010.18931580.1742915X-RAY DIFFRACTION100
5.01-33.480.24681750.20423017X-RAY DIFFRACTION100
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)
11.9492-0.24860.66391.4621-0.30143.09810.1065-0.0546-0.1398-0.11530.02820.04660.33550.1082-0.12930.14850.0113-0.03670.16070.02460.14598.70483.48410.4528
23.2519-0.32410.81471.4140.21932.39430.2882-0.2789-0.24570.0791-0.0313-0.17030.24120.0827-0.22710.2114-0.0878-0.05460.24840.01140.176342.088225.768625.1303
32.89320.0542-0.30432.6649-0.52342.40610.17840.15230.32770.11560.01120.3553-0.3528-0.3186-0.10070.18210.06090.0770.2140.03430.234111.442135.81619.5752
40.96190.7146-0.28992.1121-0.20883.12790.3888-0.61780.00450.8479-0.30110.0324-0.19660.2902-0.06590.563-0.24820.07370.62220.04930.401616.728517.436642.5681
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain B and resseq 2:201)
2X-RAY DIFFRACTION2(chain D and resseq 2:201)
3X-RAY DIFFRACTION3(chain A and resseq 0:202)
4X-RAY DIFFRACTION4(chain C and resseq 0:203)

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