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- PDB-1ld7: Co-crystal structure of Human Farnesyltransferase with farnesyldi... -

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Basic information

Entry
Database: PDB / ID: 1ld7
TitleCo-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 66
Components(protein farnesyltransferase ...) x 2
KeywordsTRANSFERASE / alpha-alpha barrel / inhibitor / ftase / pftase / fpp / caax / ras
Function / homology
Function and homology information


skeletal muscle acetylcholine-gated channel clustering / protein geranylgeranyltransferase activity / peptide pheromone maturation / protein farnesylation / protein geranylgeranyltransferase type I / CAAX-protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase complex / protein farnesyltransferase / protein farnesyltransferase activity / protein farnesyltransferase complex ...skeletal muscle acetylcholine-gated channel clustering / protein geranylgeranyltransferase activity / peptide pheromone maturation / protein farnesylation / protein geranylgeranyltransferase type I / CAAX-protein geranylgeranyltransferase activity / CAAX-protein geranylgeranyltransferase complex / protein farnesyltransferase / protein farnesyltransferase activity / protein farnesyltransferase complex / Rab geranylgeranyltransferase activity / protein geranylgeranylation / regulation of microtubule-based movement / positive regulation of skeletal muscle acetylcholine-gated channel clustering / acetyltransferase activator activity / microtubule associated complex / Apoptotic cleavage of cellular proteins / positive regulation of Rac protein signal transduction / alpha-tubulin binding / positive regulation of cell cycle / peptide binding / transforming growth factor beta receptor signaling pathway / receptor tyrosine kinase binding / lipid metabolic process / RAS processing / Inactivation, recovery and regulation of the phototransduction cascade / microtubule binding / molecular adaptor activity / Potential therapeutics for SARS / positive regulation of cell population proliferation / enzyme binding / zinc ion binding / plasma membrane / cytoplasm / cytosol
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 alpha-alpha toroid domain / 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 alpha-alpha toroid domain / 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
sucrose / FARNESYL DIPHOSPHATE / Chem-U66 / Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha / Protein farnesyltransferase subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsTaylor, J.S. / Terry, K.L. / Beese, L.S.
CitationJournal: J.Med.Chem. / Year: 2002
Title: 3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
Authors: Bell, I.M. / Gallicchio, S.N. / Abrams, M. / Beese, L.S. / Beshore, D.C. / Bhimnathwala, H. / Bogusky, M.J. / Buser, C.A. / Culberson, J.C. / Davide, J. / Ellis-Hutchings, M. / Fernandes, C. ...Authors: Bell, I.M. / Gallicchio, S.N. / Abrams, M. / Beese, L.S. / Beshore, D.C. / Bhimnathwala, H. / Bogusky, M.J. / Buser, C.A. / Culberson, J.C. / Davide, J. / Ellis-Hutchings, M. / Fernandes, C. / Gibbs, J.B. / Graham, S.L. / Hamilton, K.A. / Hartman, G.D. / Heimbrook, D.C. / Homnick, C.F. / Huber, H.E. / Huff, J.R. / Kassahun, K. / Koblan, K.S. / Kohl, N.E. / Lobell, R.B. / Lynch Jr., J.J. / Robinson, R. / Rodrigues, A.D. / Taylor, J.S. / Walsh, E.S. / Williams, T.M. / Zartman, C.B.
History
DepositionApr 8, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / entity_name_com / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.type / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_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.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_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_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Aug 16, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: protein farnesyltransferase alpha subunit
B: protein farnesyltransferase beta subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,9316
Polymers93,6872
Non-polymers1,2444
Water9,368520
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9230 Å2
ΔGint-55 kcal/mol
Surface area27970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)178.725, 178.725, 64.549
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 farnesyltransferase ... , 2 types, 2 molecules AB

#1: Protein protein farnesyltransferase alpha subunit / CAAX farnesyltransferase alpha subunit / RAS proteins prenyltransferase alpha / FTase-alpha


Mass: 44864.840 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
References: UniProt: P49354, Transferases; Transferring alkyl or aryl groups, other than methyl groups
#2: Protein protein farnesyltransferase beta subunit / CAAX farnesyltransferase beta subunit / RAS proteins prenyltransferase beta / FTase-beta


Mass: 48822.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
References: UniProt: P49356, Transferases; Transferring alkyl or aryl groups, other than methyl groups

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Sugars , 1 types, 1 molecules

#3: Polysaccharide beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose / sucrose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide with reducing-end-to-reducing-end glycosidic bond
References: sucrose
DescriptorTypeProgram
DFrufb2-1DGlcpaGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[ha122h-2b_2-5][a2122h-1a_1-5]/1-2/a2-b1WURCSPDB2Glycan 1.1.0
[][b-D-Fruf]{[(2+1)][a-D-Glcp]{}}LINUCSPDB-CARE

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Non-polymers , 4 types, 523 molecules

#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-U66 / (20S)-19,20,22,23-TETRAHYDRO-19-OXO-5H,21H-18,20-ETHANO-12,14-ETHENO-6,10-METHENOBENZ[D]IMIDAZO[4,3-L][1,6,9,13]OXATRIA ZACYCLONOADECOSINE-9-CARBONITRILE / COMPOUND 66


Mass: 453.536 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27N5O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 520 / 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: 3.17 Å3/Da / Density % sol: 61.26 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: PEG8K, NH4OAc, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 290K
Crystal grow
*PLUS
Temperature: 17 ℃ / PH range low: 5.5 / PH range high: 5.3
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
1200-400 mMammonium acetate1reservoir
212-14 %PEG80001reservoirpH5.3-5.5
310 mg/mlprotein1drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 21, 2000 / Details: mirrors
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→36.74 Å / Num. all: 76934 / Num. obs: 76934 / % possible obs: 96.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.7 % / Biso Wilson estimate: 25 Å2 / Rsym value: 0.138 / Net I/σ(I): 9.3
Reflection shellResolution: 2→2.13 Å / % possible all: 79.7
Reflection
*PLUS
Lowest resolution: 50 Å / Num. obs: 75509 / % possible obs: 94.7 % / Num. measured all: 211060 / Rmerge(I) obs: 0.09
Reflection shell
*PLUS
% possible obs: 60 % / Rmerge(I) obs: 0.247 / Mean I/σ(I) obs: 2.1

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1JCQ

1jcq


Resolution: 2→36.74 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 2465250.94 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.219 3818 5.1 %RANDOM
Rwork0.195 ---
all-76844 --
obs-75509 94.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 57.8187 Å2 / ksol: 0.400636 e/Å3
Displacement parametersBiso mean: 28.6 Å2
Baniso -1Baniso -2Baniso -3
1-0.96 Å21.93 Å20 Å2
2--0.96 Å20 Å2
3----1.92 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.35 Å0.36 Å
Refinement stepCycle: LAST / Resolution: 2→36.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5877 0 82 520 6479
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.8
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it0.671.5
X-RAY DIFFRACTIONc_mcangle_it1.152
X-RAY DIFFRACTIONc_scbond_it1.052
X-RAY DIFFRACTIONc_scangle_it1.662.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.017 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.38 521 5.1 %
Rwork0.362 9615 -
obs-9615 76.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4SUCROSE.PARSUCROSE.TOP
X-RAY DIFFRACTION5FPP.PARFPP.TAR
Refinement
*PLUS
Lowest resolution: 50 Å / Rfactor obs: 0.194 / Rfactor Rfree: 0.219 / Rfactor Rwork: 0.194
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.181
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg19.8
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.8
X-RAY DIFFRACTIONc_mcbond_it0.67
LS refinement shell
*PLUS
Rfactor Rfree: 0.38 / Rfactor Rwork: 0.362 / Rfactor obs: 0.362

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