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- PDB-3tik: Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in co... -

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Basic information

Entry
Database: PDB / ID: 3tik
TitleSterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the tipifarnib derivative 6-((4-chlorophenyl)(methoxy)(1-methyl-1H-imidazol-5-yl)methyl)-4-(2,6-difluorophenyl)-1-methylquinolin-2(1H)-one
Componentssterol 14-alpha demethylase (CYP51)
KeywordsOXIDOREDUCTASE / STEROL 14-ALPHA DEMETHYLASE / CYP51 / HEME / MONOOXYGENASE / STEROL BIOSYNTHESIS / Cytochrome P450 fold / cytochrome P450 reductase / endoplasmic reticulum membrane
Function / homology
Function and homology information


membrane biogenesis / sterol 14alpha-demethylase / sterol 14-demethylase activity / sterol metabolic process / nuclear envelope / oxidoreductase activity / iron ion binding / heme binding / endoplasmic reticulum
Similarity search - Function
: / Cytochrome P450, E-class, group IV / Cytochrome p450 / Cytochrome P450 / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-JKF / Lanosterol 14-alpha-demethylase
Similarity search - Component
Biological speciesTrypanosoma brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsHargrove, T.Y. / Wawrzak, Z. / Kraus, J.M. / Gelb, M.H. / Buckner, F.S. / Waterman, M.R. / Lepesheva, G.I.
CitationJournal: Antimicrob.Agents Chemother. / Year: 2012
Title: Pharmacological characterization, structural studies, and in vivo activities of anti-chagas disease lead compounds derived from tipifarnib.
Authors: Buckner, F.S. / Bahia, M.T. / Suryadevara, P.K. / White, K.L. / Shackleford, D.M. / Chennamaneni, N.K. / Hulverson, M.A. / Laydbak, J.U. / Chatelain, E. / Scandale, I. / Verlinde, C.L. / ...Authors: Buckner, F.S. / Bahia, M.T. / Suryadevara, P.K. / White, K.L. / Shackleford, D.M. / Chennamaneni, N.K. / Hulverson, M.A. / Laydbak, J.U. / Chatelain, E. / Scandale, I. / Verlinde, C.L. / Charman, S.A. / Lepesheva, G.I. / Gelb, M.H.
History
DepositionAug 20, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 25, 2012Group: Database references
Revision 1.2Sep 5, 2012Group: Database references
Revision 1.3Sep 13, 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_ref_seq_dif / 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_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_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_ref_seq_dif.details / _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: sterol 14-alpha demethylase (CYP51)
B: sterol 14-alpha demethylase (CYP51)
C: sterol 14-alpha demethylase (CYP51)
D: sterol 14-alpha demethylase (CYP51)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)209,70012
Polymers205,2104
Non-polymers4,4908
Water5,314295
1
C: sterol 14-alpha demethylase (CYP51)
hetero molecules

A: sterol 14-alpha demethylase (CYP51)
B: sterol 14-alpha demethylase (CYP51)
D: sterol 14-alpha demethylase (CYP51)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)209,70012
Polymers205,2104
Non-polymers4,4908
Water724
TypeNameSymmetry operationNumber
crystal symmetry operation1_645x+1,y-1,z1
identity operation1_555x,y,z1
2
A: sterol 14-alpha demethylase (CYP51)
D: sterol 14-alpha demethylase (CYP51)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,8506
Polymers102,6052
Non-polymers2,2454
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4610 Å2
ΔGint-69 kcal/mol
Surface area37680 Å2
MethodPISA
3
B: sterol 14-alpha demethylase (CYP51)
hetero molecules

C: sterol 14-alpha demethylase (CYP51)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,8506
Polymers102,6052
Non-polymers2,2454
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_645x+1,y-1,z1
Buried area4430 Å2
ΔGint-67 kcal/mol
Surface area37760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.722, 79.715, 117.521
Angle α, β, γ (deg.)74.47, 81.58, 68.05
Int Tables number1
Space group name H-MP1
DetailsAUTHORS STATE THAT THE BIOLOGICAL ASSEMBLY IN THE MEMBRANE IS A MONOMER. IN THE SOLUTION THE PROTEIN IS CRYSTALLIZED AS A TETRAMER.

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Components

#1: Protein
sterol 14-alpha demethylase (CYP51)


Mass: 51302.570 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei (eukaryote) / Gene: CYP51, Tb11.02.4080 / Plasmid: pCW / Production host: Escherichia coli (E. coli) / Strain (production host): HMS174 / References: UniProt: Q385E8, sterol 14alpha-demethylase
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-JKF / 6-[(R)-(4-chlorophenyl)(methoxy)(1-methyl-1H-imidazol-5-yl)methyl]-4-(2,6-difluorophenyl)-1-methylquinolin-2(1H)-one


Mass: 505.943 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H22ClF2N3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 295 / 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: 2.43 Å3/Da / Density % sol: 49.45 %
Crystal growTemperature: 297 K / Method: vapor diffusion / pH: 7.4
Details: POTASSIUM PHOSPHATE, SODIUM CHLORIDE, GLYCEROL, PEG 5000, n-TETRADECYL-BETA-D-MALTOSIDE, 6-((4-CHLOROPHENYL)(METHOXY)(1-METHYL-1H-IMIDAZOL-YL)METHYL)-4-(2,6-DIFLUOROPHENYL)-1-METHYLQUINOLIN- ...Details: POTASSIUM PHOSPHATE, SODIUM CHLORIDE, GLYCEROL, PEG 5000, n-TETRADECYL-BETA-D-MALTOSIDE, 6-((4-CHLOROPHENYL)(METHOXY)(1-METHYL-1H-IMIDAZOL-YL)METHYL)-4-(2,6-DIFLUOROPHENYL)-1-METHYLQUINOLIN-2(1H)-ONE, pH 7.4, VAPOR DIFFUSION, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 7, 2011 / Details: Be Lenses/Diamond Laue Mono
RadiationMonochromator: Diamond / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. all: 122058 / Num. obs: 115222 / % possible obs: 94 % / Observed criterion σ(F): 2.8 / Observed criterion σ(I): 2.8 / Redundancy: 6 % / Biso Wilson estimate: 38.7 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 43.6
Reflection shellResolution: 2.05→2.09 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.695 / Mean I/σ(I) obs: 2.8 / Num. unique all: 8174 / % possible all: 95.4

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERfor MRphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3g1q

3g1q


Resolution: 2.05→30 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.943 / SU B: 12.35 / SU ML: 0.15 / Cross valid method: THROUGHOUT / ESU R Free: 0.183 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24338 6082 5 %RANDOM
Rwork0.18593 ---
all0.18887 122058 --
obs0.18887 115222 99.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 49.848 Å2
Baniso -1Baniso -2Baniso -3
1-0.88 Å2-0.23 Å20.9 Å2
2---1.21 Å2-0.65 Å2
3---0.58 Å2
Refinement stepCycle: LAST / Resolution: 2.05→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14300 0 316 295 14911
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02214988
X-RAY DIFFRACTIONr_angle_refined_deg1.1352.02320344
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.31551796
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.13223.252652
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.457152628
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.82815120
X-RAY DIFFRACTIONr_chiral_restr0.0790.22192
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02111340
X-RAY DIFFRACTIONr_mcbond_it1.9631.59020
X-RAY DIFFRACTIONr_mcangle_it3.311214632
X-RAY DIFFRACTIONr_scbond_it5.14735968
X-RAY DIFFRACTIONr_scangle_it7.8414.55712
X-RAY DIFFRACTIONr_rigid_bond_restr2.838314988
LS refinement shellResolution: 2.05→2.099 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.321 420 -
Rwork0.228 8174 -
obs--95.44 %

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