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- PDB-4g7g: Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in co... -

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Basic information

Entry
Database: PDB / ID: 4g7g
TitleSterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the VNI derivative (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide [VNI/VNF (VFV)]
Componentssterol 14-alpha-demethylase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / cytochrome P450 fold / heme / monooxygenase / sterol biosynthesis / eukaryotic membrane biogenesis / cytochrome P450 reductase / endoplasmic reticulum membrane / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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-VFV / 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. / Waterman, M.R. / Lepesheva, G.I.
CitationJournal: J Infect Dis / Year: 2015
Title: VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis.
Authors: Lepesheva, G.I. / Hargrove, T.Y. / Rachakonda, G. / Wawrzak, Z. / Pomel, S. / Cojean, S. / Nde, P.N. / Nes, W.D. / Locuson, C.W. / Calcutt, M.W. / Waterman, M.R. / Daniels, J.S. / Loiseau, P.M. / Villalta, F.
History
DepositionJul 20, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2015Group: Database references
Revision 1.2Oct 28, 2015Group: 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
B: sterol 14-alpha-demethylase
C: sterol 14-alpha-demethylase
D: sterol 14-alpha-demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)207,69612
Polymers203,0404
Non-polymers4,6568
Water9,080504
1
A: sterol 14-alpha-demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9243
Polymers50,7601
Non-polymers1,1642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: sterol 14-alpha-demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9243
Polymers50,7601
Non-polymers1,1642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: sterol 14-alpha-demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9243
Polymers50,7601
Non-polymers1,1642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: sterol 14-alpha-demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9243
Polymers50,7601
Non-polymers1,1642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.947, 79.706, 117.868
Angle α, β, γ (deg.)74.64, 81.20, 68.96
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
sterol 14-alpha-demethylase / CYP51


Mass: 50759.902 Da / Num. of mol.: 4 / Fragment: UNP residues 29-476 / Mutation: P29G, T30K, D31L
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-VFV / N-[(1R)-1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide


Mass: 547.554 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H23F2N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 504 / 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: 2.49 Å3/Da / Density % sol: 50.63 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: potassium phosphate, sodium chloride, glycerol, PEG3350, N-tetradecyl-beta-D-maltoside, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 294K

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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: Apr 3, 2012 / Details: Be Lenses/Diamond Laue Mono
RadiationMonochromator: Diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.05→29.817 Å / Num. all: 123297 / Num. obs: 120831 / % possible obs: 98 % / Observed criterion σ(F): 2.6 / Observed criterion σ(I): 2.6 / Redundancy: 4.6 % / Biso Wilson estimate: 37.85 Å2 / Rmerge(I) obs: 0.046 / Rsym value: 0.046 / Net I/σ(I): 31
Reflection shellResolution: 2.05→2.09 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 2.6 / Num. unique all: 5970 / % possible all: 97

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3G1Q

3g1q


Resolution: 2.05→29.817 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.95 / SU B: 11.406 / SU ML: 0.137 / Cross valid method: THROUGHOUT / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.22618 6065 5 %RANDOM
Rwork0.1627 ---
obs0.16597 114765 98.03 %-
all-117107 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.796 Å2
Baniso -1Baniso -2Baniso -3
1-0.91 Å2-0.72 Å20.32 Å2
2---0.6 Å20.04 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 2.05→29.817 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14228 0 336 504 15068
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0214940
X-RAY DIFFRACTIONr_angle_refined_deg1.9762.00420272
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.38551788
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.07323.252652
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.321152596
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.93615120
X-RAY DIFFRACTIONr_chiral_restr0.0760.22184
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02111364
X-RAY DIFFRACTIONr_rigid_bond_restr2.287314940
X-RAY DIFFRACTIONr_sphericity_free20.985159
X-RAY DIFFRACTIONr_sphericity_bonded16.799514911
LS refinement shellResolution: 2.05→2.102 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 452 -
Rwork0.205 8323 -
obs--95.9 %

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