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- PDB-4uvr: Binding mode, selectivity and potency of N-indolyl-oxopyridinyl-4... -

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Basic information

Entry
Database: PDB / ID: 4uvr
TitleBinding mode, selectivity and potency of N-indolyl-oxopyridinyl-4- amino-propanyl-based inhibitors targeting Trypanosoma cruzi CYP51
ComponentsSTEROL 14-DEMETHYLASE, CYP51
KeywordsOXIDOREDUCTASE / CYP51 / STEROL 14-DEMETHYLASE / 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-J5Y / Sterol 14-alpha demethylase / Sterol 14-alpha demethylase
Similarity search - Component
Biological speciesTRYPANOSOMA CRUZI (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsVieira, D.F. / Choi, J.Y. / Calvet, C.M. / Gut, J. / Kellar, D. / Siqueira-Neto, J.L. / Johnston, J.B. / 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 8, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 26, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 14, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: 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 / pdbx_struct_special_symmetry / 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-DEMETHYLASE, CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8997
Polymers53,2871
Non-polymers1,6126
Water59433
1
A: STEROL 14-DEMETHYLASE, CYP51
hetero molecules

A: STEROL 14-DEMETHYLASE, CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,79714
Polymers106,5742
Non-polymers3,22412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation11_554-x+y,y,-z-1/21
Buried area7640 Å2
ΔGint-192.2 kcal/mol
Surface area35410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)128.115, 128.115, 117.781
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number182
Space group name H-MP6322
Components on special symmetry positions
IDModelComponents
11A-1479-

SO4

21A-2001-

HOH

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Components

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


Mass: 53286.820 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 32-481
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) TRYPANOSOMA CRUZI (eukaryote) / Plasmid: PCW / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): HMS174
References: UniProt: Q5I4E1, UniProt: Q7Z1V1*PLUS, sterol 14alpha-demethylase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-J5Y / Nalpha-{4-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]-2-fluorobenzoyl}-N-pyridin-4-yl-D-tryptophanamide


Mass: 611.108 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32ClFN6O2
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O
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: 2.58 Å3/Da / Density % sol: 52.42 % / Description: NONE
Crystal growpH: 5.6
Details: 0.1 M SODIUM ACETATE PH 5.6, 0.25 M AMMONIUM SULFATE, 25% PEG 3350

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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 30, 2014 / 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: 2.48→117.78 Å / Num. obs: 20811 / % possible obs: 100 % / Observed criterion σ(I): 0.5 / Redundancy: 15.2 % / Biso Wilson estimate: 55.7 Å2 / Rmerge(I) obs: 0.22 / Net I/σ(I): 11.5
Reflection shellResolution: 2.48→2.61 Å / Redundancy: 15.6 % / Mean I/σ(I) obs: 1.8 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4C0C

4c0c


Resolution: 2.48→110.95 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.926 / SU B: 9.855 / SU ML: 0.212 / Cross valid method: THROUGHOUT / ESU R: 0.383 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2525 1001 4.8 %RANDOM
Rwork0.19181 ---
obs0.19479 19783 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.053 Å2
Baniso -1Baniso -2Baniso -3
1--1.09 Å2-0.55 Å20 Å2
2---1.09 Å20 Å2
3---3.54 Å2
Refinement stepCycle: LAST / Resolution: 2.48→110.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3397 0 107 33 3537
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0193595
X-RAY DIFFRACTIONr_bond_other_d0.0020.023388
X-RAY DIFFRACTIONr_angle_refined_deg1.6872.0024900
X-RAY DIFFRACTIONr_angle_other_deg0.85937763
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2985437
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.1123.356146
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.85115574
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0431523
X-RAY DIFFRACTIONr_chiral_restr0.0950.2538
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214033
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02832
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_it2.7774.0031754
X-RAY DIFFRACTIONr_mcbond_other2.7684.0011753
X-RAY DIFFRACTIONr_mcangle_it4.2396.0012189
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.3984.3441840
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: 2.48→2.544 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 82 -
Rwork0.328 1410 -
obs--99.8 %

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