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- PDB-8e9e: Rat protein farnesyltransferase in complex with FPP and inhibitor 2f -

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Basic information

Entry
Database: PDB / ID: 8e9e
TitleRat protein farnesyltransferase in complex with FPP and inhibitor 2f
Components
  • Protein farnesyltransferase subunit beta
  • Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Protein prenylyltransferase / Antifungal / TRANSFERASE / TRANSFERASE-Inhibitor complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Apoptotic cleavage of cellular proteins / Inactivation, recovery and regulation of the phototransduction cascade / RAS processing / protein geranylgeranyltransferase activity / protein geranylgeranyltransferase type I / CAAX-protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase complex / protein farnesylation / positive regulation of tubulin deacetylation / protein farnesyltransferase ...Apoptotic cleavage of cellular proteins / Inactivation, recovery and regulation of the phototransduction cascade / RAS processing / protein geranylgeranyltransferase activity / protein geranylgeranyltransferase type I / CAAX-protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase complex / protein farnesylation / positive regulation of tubulin deacetylation / protein farnesyltransferase / protein farnesyltransferase activity / protein farnesyltransferase complex / regulation of fibroblast proliferation / Rab geranylgeranyltransferase activity / protein geranylgeranylation / positive regulation of skeletal muscle acetylcholine-gated channel clustering / negative regulation of nitric-oxide synthase biosynthetic process / farnesyltranstransferase activity / microtubule associated complex / enzyme-linked receptor protein signaling pathway / positive regulation of nitric-oxide synthase biosynthetic process / positive regulation of Rac protein signal transduction / alpha-tubulin binding / : / positive regulation of cell cycle / response to cytokine / wound healing / response to organic cyclic compound / lipid metabolic process / receptor tyrosine kinase binding / positive regulation of fibroblast proliferation / fibroblast proliferation / microtubule binding / cell population proliferation / molecular adaptor activity / negative regulation of cell population proliferation / positive regulation of cell population proliferation / negative regulation of apoptotic process / zinc ion binding / cytoplasm
Similarity search - Function
Protein farnesyltransferase subunit beta / Prenyltransferase subunit beta / Protein prenyltransferase, alpha subunit / Protein prenyltransferase alpha subunit repeat / Protein prenyltransferases alpha subunit repeat profile. / PFTB repeat / Prenyltransferase and squalene oxidase repeat / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid
Similarity search - Domain/homology
FARNESYL DIPHOSPHATE / Chem-XMY / Protein farnesyltransferase subunit beta / Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.844 Å
AuthorsWang, Y. / Shi, Y. / Beese, L.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5P01AI104533 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase.
Authors: Wang, Y. / Xu, F. / Nichols, C.B. / Shi, Y. / Hellinga, H.W. / Alspaugh, J.A. / Distefano, M.D. / Beese, L.S.
History
DepositionAug 26, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2022Group: 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
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
B: Protein farnesyltransferase subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,88118
Polymers92,8202
Non-polymers2,06016
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9930 Å2
ΔGint3 kcal/mol
Surface area29830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)169.898, 169.898, 69.339
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 , 2 types, 2 molecules AB

#1: Protein Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha / CAAX farnesyltransferase subunit alpha / FTase-alpha / Ras proteins prenyltransferase subunit alpha ...CAAX farnesyltransferase subunit alpha / FTase-alpha / Ras proteins prenyltransferase subunit alpha / Type I protein geranyl-geranyltransferase subunit alpha / GGTase-I-alpha


Mass: 44098.145 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Fnta / Production host: Escherichia coli (E. coli)
References: UniProt: Q04631, protein farnesyltransferase, protein geranylgeranyltransferase type I
#2: Protein Protein farnesyltransferase subunit beta / FTase-beta / CAAX farnesyltransferase subunit beta / Ras proteins prenyltransferase subunit beta


Mass: 48722.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Fntb / Production host: Escherichia coli (E. coli) / References: UniProt: Q02293, protein farnesyltransferase

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Non-polymers , 6 types, 146 molecules

#3: Chemical
ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-FPP / FARNESYL DIPHOSPHATE


Mass: 382.326 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H28O7P2
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Chemical ChemComp-XMY / (5S)-4-({1-[(4-bromophenyl)methyl]-1H-imidazol-5-yl}methyl)-5-butyl-1-[3-(trifluoromethoxy)phenyl]piperazin-2-one


Mass: 565.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28BrF3N4O2 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3.11 Å3/Da / Density % sol: 60.48 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 50-150mM Na Acetate pH 5.5, 1-2.5% PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.116 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.116 Å / Relative weight: 1
ReflectionResolution: 2.844→43.38 Å / Num. obs: 26864 / % possible obs: 99 % / Redundancy: 5.8 % / CC1/2: 0.991 / CC star: 0.998 / Rmerge(I) obs: 0.1562 / Rpim(I) all: 0.0666 / Rrim(I) all: 0.1712 / Net I/σ(I): 10.49
Reflection shellResolution: 2.844→2.946 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.7442 / Mean I/σ(I) obs: 1.98 / Num. unique obs: 2626 / CC1/2: 0.679 / CC star: 0.899 / Rpim(I) all: 0.3233 / Rrim(I) all: 0.8176 / % possible all: 97.8

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Starting model: 3.0E+33 / Resolution: 2.844→43.38 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.194 1986 7.36 %
Rwork0.1758 47267 -
obs0.1772 26858 96.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 112.88 Å2 / Biso mean: 46.9063 Å2 / Biso min: 24.82 Å2
Refinement stepCycle: final / Resolution: 2.844→43.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5948 0 129 130 6207
Biso mean--52.28 46.33 -
Num. residues----730
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.8442-2.88020.27821410.307167189
2.8802-2.91810.32471300.2714169896
2.9181-2.95810.3321330.2714174397
2.9581-3.00030.28241440.2839177298
3.0003-3.04510.29891360.2682177598
3.0451-3.09270.29591390.2666175198
3.0927-3.14340.28821450.2449178999
3.1434-3.19760.2631420.2402176198
3.1976-3.25570.28951420.215173098
3.2557-3.31830.18381480.2161182198
3.3183-3.3860.20291480.2042174998
3.386-3.45960.20531510.1908177398
3.4596-3.540.19551370.1878177398
3.54-3.62850.20391370.1826172597
3.6285-3.72660.20531290.1659176197
3.7266-3.83620.15491360.154179098
3.8362-3.95990.20731330.1434171297
3.9599-4.10130.15241360.1443174697
4.1013-4.26540.14081490.1387178598
4.2654-4.45930.12791380.13176798
4.4593-4.69420.13621310.1309178298
4.6942-4.98790.17511490.1343177697
4.9879-5.37240.15651330.156175097
5.3724-5.91180.15851350.1531174897
5.9118-6.76450.19531370.1667169695
6.7645-8.5120.13781340.1502167393
8.512-43.380.20291430.1536175097

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