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- PDB-3ksq: Discovery of C-Imidazole Azaheptapyridine FPT Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3ksq
TitleDiscovery of C-Imidazole Azaheptapyridine FPT Inhibitors
Components
  • Farnesyltransferase, CAAX box, alpha
  • Protein farnesyltransferase subunit beta
KeywordsTRANSFERASE / PRENYLTRANSFERASE / Metal-binding / Phosphoprotein
Function / homology
Function and homology information


skeletal muscle acetylcholine-gated channel clustering / Apoptotic cleavage of cellular proteins / Inactivation, recovery and regulation of the phototransduction cascade / RAS processing / protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase complex / protein farnesylation / protein geranylgeranyltransferase type I / positive regulation of tubulin deacetylation ...skeletal muscle acetylcholine-gated channel clustering / Apoptotic cleavage of cellular proteins / Inactivation, recovery and regulation of the phototransduction cascade / RAS processing / protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase complex / protein farnesylation / protein geranylgeranyltransferase type I / positive regulation of tubulin deacetylation / protein farnesyltransferase / protein farnesyltransferase activity / protein farnesyltransferase complex / Rab geranylgeranyltransferase activity / regulation of fibroblast proliferation / protein geranylgeranylation / positive regulation of skeletal muscle acetylcholine-gated channel clustering / : / farnesyltranstransferase activity / microtubule associated complex / enzyme-linked receptor protein signaling pathway / : / positive regulation of Rac protein signal transduction / alpha-tubulin binding / positive regulation of cell cycle / response to cytokine / wound healing / lipid metabolic process / receptor tyrosine kinase binding / response to organic cyclic compound / 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 / plasma membrane / cytoplasm
Similarity search - Function
Protein farnesyltransferase subunit beta / Protein prenylyltransferase / 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 / Glycosyltransferase - #20 / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid ...Protein farnesyltransferase subunit beta / Protein prenylyltransferase / 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 / Glycosyltransferase - #20 / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Glycosyltransferase / Alpha/alpha barrel / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Mainly Alpha
Similarity search - Domain/homology
FARNESYL DIPHOSPHATE / Chem-Z96 / Protein farnesyltransferase subunit beta / Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha / Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsZhu, H.Y. / Cooper, A.B. / Njoroge, G. / Kirschmeier, P. / Strickland, C. / Hruza, A. / Girijavallabhan, V.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery of C-imidazole azaheptapyridine FPT inhibitors.
Authors: Zhu, H.Y. / Cooper, A.B. / Desai, J. / Njoroge, G. / Kirschmeier, P. / Bishop, W.R. / Strickland, C. / Hruza, A. / Doll, R.J. / Girijavallabhan, V.M.
History
DepositionNov 23, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Farnesyltransferase, CAAX box, alpha
B: Protein farnesyltransferase subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,8026
Polymers92,8082
Non-polymers9944
Water5,386299
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6640 Å2
ΔGint-21 kcal/mol
Surface area28480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)171.122, 171.122, 69.269
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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 Farnesyltransferase, CAAX box, alpha


Mass: 44086.090 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: Q5RKJ4, UniProt: Q04631*PLUS, protein farnesyltransferase
#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 , 5 types, 303 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-FPP / FARNESYL DIPHOSPHATE


Mass: 382.326 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H28O7P2
#6: Chemical ChemComp-Z96 / tert-butyl 4-{(11S)-8-chloro-6-[(R)-hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl}piperazine-1-carboxylate / 1,1-DIMETHYLETHYL 4-[8-CHLORO-6-[HYDROXY(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-11H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11(S)-YL]-1-PIPERAZINECARBOXYLATE


Mass: 522.038 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32ClN5O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / Source method: isolated from a natural source / Formula: H2O

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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: 3.15 Å3/Da / Density % sol: 61.01 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.7
Details: PEG 4000, SODIUM ACETATE, KCL, pH 5.7, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Jun 21, 2009 / Details: VARIMAX MULTI-LAYER OPTICS
RadiationMonochromator: VARIMAX MULTI-LAYER OPTICS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→29.64 Å / Num. all: 68055 / Num. obs: 67917 / % possible obs: 99.8 % / Redundancy: 4.5 % / Biso Wilson estimate: 39.66 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 12.9
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.564 / Mean I/σ(I) obs: 2.5 / Num. unique all: 3333 / % possible all: 99.6

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Processing

Software
NameVersionClassification
StructureStudiodata collection
BUSTER2.9.2refinement
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.9.2phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1O5M

1o5m


Resolution: 2.1→29.64 Å / Cross valid method: THROUGHOUT / σ(F): 0
Stereochemistry target values: STANDARD AMINO ACID DICTIONARY. BONDS AND ANGLES FROM ENGH AND HUBER EH99. OTHER VALUES BASED ON PREVIOUS TNT OR TAKEN FROM CCP4.
RfactorNum. reflection% reflectionSelection details
Rfree0.2188 3413 5.07 %RANDOM
Rwork0.1926 ---
obs-67377 --
Displacement parametersBiso mean: 43 Å2
Baniso -1Baniso -2Baniso -3
1--3.1056 Å20 Å20 Å2
2---3.1056 Å20 Å2
3---6.2112 Å2
Refine analyzeLuzzati coordinate error obs: 0.261 Å
Refinement stepCycle: LAST / Resolution: 2.1→29.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5849 0 63 299 6211
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_bond_d0.01
X-RAY DIFFRACTIONo_angle_deg1
LS refinement shellResolution: 2.1→2.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2801 256 5.19 %
Rwork0.2325 4676 -
obs-4932 -

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