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- PDB-4c28: Crystal structure of Trypanosoma cruzi CYP51 bound to the inhibit... -

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Basic information

Entry
Database: PDB / ID: 4c28
TitleCrystal structure of Trypanosoma cruzi CYP51 bound to the inhibitor (R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.
ComponentsSTEROL 14-ALPHA DEMETHYLASE
KeywordsOXIDOREDUCTASE / STEROL BIOSYNTHESIS / CHAGAS DISEASE
Function / homology
Function and homology information


sterol 14alpha-demethylase / sterol 14-demethylase activity / steroid 7-alpha-hydroxylase activity / oxysterol 7-alpha-hydroxylase activity / sterol biosynthetic process / bile acid biosynthetic process / cholesterol homeostasis / iron ion binding / heme binding / membrane
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-TW5 / Sterol 14-alpha demethylase
Similarity search - Component
Biological speciesTRYPANOSOMA CRUZI (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsVieira, D.F. / Calvet, C.M. / Choi, J.Y. / Cameron, M.D. / Gut, J. / Kellar, D. / Siqueira-Neto, J.L. / McKerrow, J.H. / Roush, W.R. / Podust, L.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Binding Mode and Potency of N-Indolyl-Oxopyridinyl-4-Amino-Propanyl-Based Inhibitors Targeting Trypanosoma Cruzi Cyp51
Authors: Vieira, D.F. / Choi, J.Y. / Calvet, C.M. / Siqueira-Neto, J.L. / Johnston, J.B. / Kellar, D. / Gut, J. / Cameron, M.D. / Mckerrow, J.H. / Roush, W.R. / Podust, L.M.
History
DepositionAug 16, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2014Group: Database references
Revision 1.2Jan 14, 2015Group: Database references
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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

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Assembly

Deposited unit
A: STEROL 14-ALPHA DEMETHYLASE
B: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,1268
Polymers106,6012
Non-polymers2,5256
Water7,386410
1
A: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,6125
Polymers53,3011
Non-polymers1,3114
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,5143
Polymers53,3011
Non-polymers1,2142
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.951, 79.005, 176.839
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein STEROL 14-ALPHA DEMETHYLASE / TC14DM / CYTOCHROME P450 51 / LANOSTEROL 14-ALPHA DEMETHYLASE / CYP51


Mass: 53300.738 Da / Num. of mol.: 2 / Fragment: RESIDUES 29-481
Source method: isolated from a genetically manipulated source
Details: 32 N-TERMINUS RESIDUES ARE REPLACED WITH THE SEQUENCE MAKKTSSKGKL 6XHIS TAG ENGINEERED AT THE C-TERMINUS
Source: (gene. exp.) TRYPANOSOMA CRUZI (eukaryote) / Plasmid: PCW / Production host: ESCHERICHIA COLI K-12 (bacteria) / Variant (production host): HMS174(DE3) / References: UniProt: Q7Z1V1, sterol 14alpha-demethylase

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Non-polymers , 5 types, 416 molecules

#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-TW5 / (R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide


Mass: 597.082 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H30ClFN6O2
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 410 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsFIRST 32 RESIDUES AT THE N-TERMINUS ARE REPLACED WITH THE MAKKTSSKGKL SEQUENCE, 6XHIS TAG ...FIRST 32 RESIDUES AT THE N-TERMINUS ARE REPLACED WITH THE MAKKTSSKGKL SEQUENCE, 6XHIS TAG ENGINEERED AT THE C- TERMINUS.

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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: 2.36 Å3/Da / Density % sol: 47.9 % / Description: NONE
Crystal growpH: 4.5
Details: 0.4 M AMMONIUM ACETATE, 0.1 M SODIUM ACETATE PH 4.5, 28% PEG 3350, 5% JEFFAMINE M-600 PH 7.0

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11587
DetectorType: MARRESERCH / Detector: CCD / Date: Jul 26, 2013 / Details: MIRRORS
RadiationMonochromator: SI (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11587 Å / Relative weight: 1
ReflectionResolution: 2.04→176.84 Å / Num. obs: 56809 / % possible obs: 86.4 % / Observed criterion σ(I): 0.5 / Redundancy: 3.5 % / Biso Wilson estimate: 28.6 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 9.9
Reflection shellResolution: 2.04→2.15 Å / Redundancy: 2 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 1.6 / % possible all: 47.8

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4C0C

4c0c


Resolution: 2.03→72.24 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.919 / SU B: 4.473 / SU ML: 0.121 / Cross valid method: THROUGHOUT / ESU R: 0.233 / ESU R Free: 0.195 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23761 2904 5.1 %RANDOM
Rwork0.18574 ---
obs0.18836 54178 85.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.021 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20 Å2
2--1.31 Å20 Å2
3----1.36 Å2
Refinement stepCycle: LAST / Resolution: 2.03→72.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7033 0 177 410 7620
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0197529
X-RAY DIFFRACTIONr_bond_other_d0.0020.027195
X-RAY DIFFRACTIONr_angle_refined_deg1.9112.01110225
X-RAY DIFFRACTIONr_angle_other_deg0.906316530
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3715886
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.68923.252329
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.471151273
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3491559
X-RAY DIFFRACTIONr_chiral_restr0.1050.21080
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0218439
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021792
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.9012.3073547
X-RAY DIFFRACTIONr_mcbond_other1.8982.3063546
X-RAY DIFFRACTIONr_mcangle_it2.8093.4464436
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.732.5963982
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.03→2.083 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.399 85 -
Rwork0.314 1885 -
obs--40.59 %

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