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

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Basic information

Entry
Database: PDB / ID: 4bmm
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)-2',3, 5'-trifluoro-(1,1'-biphenyl)-4-carboxamide
ComponentsSTEROL 14-ALPHA DEMETHYLASE
KeywordsOXIDOREDUCTASE / STEROL BIOSYNTHESIS / CHAGAS DISEASE
Function / homology
Function and homology information


sterol 14-demethylase activity / sterol biosynthetic process / sterol 14alpha-demethylase / 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-TU1 / Sterol 14-alpha demethylase
Similarity search - Component
Biological speciesTRYPANOSOMA CRUZI (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsChoi, J.Y. / Calvet, C.M. / Gunatilleke, S.S. / Roush, W.R. / McKerrow, J.H. / Podust, L.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: 4-Aminopyridyl-Based Cyp51 Inhibitors as Anti-Trypanosoma Cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency.
Authors: Calvet, C.M. / Vieira, D.F. / Choi, J.Y. / Kellar, D. / Cameron, M.D. / Siqueira-Neto, J.L. / Gut, J. / Johnston, J.B. / Lin, L. / Khan, S. / Mckerrow, J.H. / Roush, W.R. / Podust, L.M.
History
DepositionMay 9, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 11, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 20, 2014Group: Database references / Other
Revision 1.2Sep 10, 2014Group: 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 / pdbx_struct_conn_angle / struct_conn / 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 / _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.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_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_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_conn.ptnr2_label_seq_id / _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)217,67112
Polymers213,1474
Non-polymers4,5248
Water68538
1
B: STEROL 14-ALPHA DEMETHYLASE
D: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,8366
Polymers106,5742
Non-polymers2,2624
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4550 Å2
ΔGint-70.7 kcal/mol
Surface area35360 Å2
MethodPISA
2
A: STEROL 14-ALPHA DEMETHYLASE
C: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,8366
Polymers106,5742
Non-polymers2,2624
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-68.7 kcal/mol
Surface area35170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)272.469, 66.452, 122.219
Angle α, β, γ (deg.)90.00, 110.65, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 53286.820 Da / Num. of mol.: 4 / Fragment: RESIDUES 32-481
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) TRYPANOSOMA CRUZI (eukaryote) / Strain: CL BRENER / Plasmid: PCW / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): K-12 / Variant (production host): HMS174(DE3) / References: UniProt: Q7Z1V1, 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-TU1 / 4-[2,5-bis(fluoranyl)phenyl]-2-fluoranyl-N-[(2R)-3-(1H-indol-3-yl)-1-oxidanylidene-1-(pyridin-4-ylamino)propan-2-yl]benzamide


Mass: 514.498 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H21F3N4O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsPROTOPORPHYRIN IX CONTAINING FE (HEM): HEME THIOLATE BOUND TO CYS 422
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: 2.4 Å3/Da / Density % sol: 48.7 % / Description: NONE
Crystal growpH: 5.5
Details: 0.1 M AMMONIUM ACETATE, 0.1 M BIS-TRIS PH 5.5, 17% PEG 10K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11587
DetectorType: MARRESEARCH / Detector: CCD / Date: Sep 29, 2012 / 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: 2.84→127.48 Å / Num. obs: 48741 / % possible obs: 99.9 % / Observed criterion σ(I): 1.5 / Redundancy: 3.8 % / Biso Wilson estimate: 83.9 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 7
Reflection shellResolution: 2.84→2.99 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.72 / Mean I/σ(I) obs: 1.5 / % possible all: 99.9

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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 2YMC

2ymc
PDB Unreleased entry


Resolution: 2.84→114.63 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.903 / SU B: 50.234 / SU ML: 0.426 / Cross valid method: THROUGHOUT / ESU R Free: 0.463 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29005 2469 5.1 %RANDOM
Rwork0.18908 ---
obs0.19427 46238 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.461 Å2
Baniso -1Baniso -2Baniso -3
1--2.95 Å20 Å2-0.17 Å2
2--6.66 Å20 Å2
3----2.84 Å2
Refinement stepCycle: LAST / Resolution: 2.84→114.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13726 0 324 38 14088
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01914434
X-RAY DIFFRACTIONr_bond_other_d0.0020.0213657
X-RAY DIFFRACTIONr_angle_refined_deg1.571.99319639
X-RAY DIFFRACTIONr_angle_other_deg0.85331336
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.84551757
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.05423.405602
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.775152359
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9631598
X-RAY DIFFRACTIONr_chiral_restr0.080.22134
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02116249
X-RAY DIFFRACTIONr_gen_planes_other0.0030.023359
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_it5.3163.7597052
X-RAY DIFFRACTIONr_mcbond_other5.3163.7587051
X-RAY DIFFRACTIONr_mcangle_it7.1595.6258801
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it5.0283.827382
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_restr2.861328091
X-RAY DIFFRACTIONr_sphericity_free81.608525
X-RAY DIFFRACTIONr_sphericity_bonded24.66527727
LS refinement shellResolution: 2.84→2.914 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 192 -
Rwork0.301 3384 -
obs--99.44 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.22180.1152-0.18030.0754-0.07690.45110.0002-0.06670.0002-0.030.0189-0.04890.0175-0.1079-0.01910.4692-0.02380.00390.5181-0.0030.492-55.8827-33.10612.1997
20.35650.2108-0.3620.1372-0.20050.40680.00070.02990.04610.0150.0028-0.0086-0.0224-0.055-0.00350.4727-0.0152-0.0060.6111-0.00360.4499-96.6398-50.778241.5366
30.1934-0.01830.07840.2164-0.14130.11690.0073-0.0376-0.015-0.01670.01920.01140.01030.0017-0.02660.46250.00220.01460.6281-0.01890.4645-37.8003-20.734647.0214
40.3237-0.11370.06190.04520.00640.2701-0.0232-0.09550.00950.00090.01070.01430.03670.00930.01240.4601-0.00540.02190.54460.00390.5081-126.4915-66.125116.9606
50.1202-0.0260.01620.0150.00370.05940.0295-0.0509-0.0249-0.06230.00030.0529-0.01970.0321-0.02980.5876-0.027-0.00620.0519-0.04850.6234-66.3862-33.371121.6124
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A30 - 1460
2X-RAY DIFFRACTION2B30 - 1460
3X-RAY DIFFRACTION3C30 - 1460
4X-RAY DIFFRACTION4D30 - 1460
5X-RAY DIFFRACTION5A2001 - 2013
6X-RAY DIFFRACTION5B2001 - 2007
7X-RAY DIFFRACTION5C2001 - 2009
8X-RAY DIFFRACTION5D2001 - 2009

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