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- PDB-7rtq: Sterol 14alpha demethylase (CYP51) from Naegleria fowleri in comp... -

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Basic information

Entry
Database: PDB / ID: 7rtq
TitleSterol 14alpha demethylase (CYP51) from Naegleria fowleri in complex with an inhibitor R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide
ComponentsProtein CYP51
KeywordsOXIDOREDUCTASE / CYTOCHROME P450 / CYP51 / sterol 14 alpha- demethylase
Function / homology
Function and homology information


oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / monooxygenase activity / iron ion binding / heme binding
Similarity search - Function
: / Cytochrome P450, E-class, group IV / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
Chem-7PW / PROTOPORPHYRIN IX CONTAINING FE / CYP51, sterol 14alpha-demethylase
Similarity search - Component
Biological speciesNaegleria fowleri (brain-eating amoeba)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsLepesheva, G.I. / Hargrove, T.Y. / Wawrzak, Z.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM067871 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Relaxed Substrate Requirements of Sterol 14 alpha-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition.
Authors: Hargrove, T.Y. / Wawrzak, Z. / Rachakonda, G. / Nes, W.D. / Villalta, F. / Guengerich, F.P. / Lepesheva, G.I.
History
DepositionAug 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein CYP51
B: Protein CYP51
C: Protein CYP51
D: Protein CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)218,96812
Polymers214,2404
Non-polymers4,7288
Water16,952941
1
A: Protein CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7423
Polymers53,5601
Non-polymers1,1822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Protein CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7423
Polymers53,5601
Non-polymers1,1822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Protein CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7423
Polymers53,5601
Non-polymers1,1822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Protein CYP51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7423
Polymers53,5601
Non-polymers1,1822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.062, 75.223, 105.953
Angle α, β, γ (deg.)89.490, 74.630, 63.980
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: _ / Auth seq-ID: 35 - 483 / Label seq-ID: 10 - 458

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Protein CYP51


Mass: 53559.992 Da / Num. of mol.: 4 / Fragment: 6 His tag added to the C-terminus / Mutation: N33K, E34L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Naegleria fowleri (brain-eating amoeba)
Gene: NF0102700 / Production host: Escherichia coli (E. coli) / Strain (production host): HMS-174 / References: UniProt: A0A2H4A2U9
#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-7PW / N-[(1R)-2-(1H-imidazol-1-yl)-1-(3,4',5-trifluoro[1,1'-biphenyl]-4-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide


Mass: 565.545 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H22F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 941 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.34 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.34 mM n-Dodecyl-beta-D-maltoside, 5.54 mM TCEP, 15% PEG 3350 (w/v), 5% isopropanol , 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 22, 2021 / Details: Be lens
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.11→67.08 Å / Num. obs: 113996 / % possible obs: 96.8 % / Redundancy: 3.3 % / Biso Wilson estimate: 23.3 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.073 / Rrim(I) all: 0.099 / Net I/σ(I): 8.6
Reflection shellResolution: 2.11→2.2 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.414 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 16740 / CC1/2: 0.778 / Rpim(I) all: 0.339 / Rrim(I) all: 0.613 / % possible all: 97

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3g1q

3g1q


Resolution: 2.11→64.63 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.916 / SU B: 13.738 / SU ML: 0.155 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.2 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2373 5725 5.2 %RANDOM
Rwork0.2113 ---
obs0.2127 105350 96.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 126.85 Å2 / Biso mean: 28.549 Å2 / Biso min: 8.16 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å2-0.03 Å20.08 Å2
2--0.1 Å20.02 Å2
3---0.01 Å2
Refinement stepCycle: final / Resolution: 2.11→64.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14468 0 508 941 15917
Biso mean--18.75 35.45 -
Num. residues----1796
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01315356
X-RAY DIFFRACTIONr_bond_other_d0.0170.01714708
X-RAY DIFFRACTIONr_angle_refined_deg1.4491.7120780
X-RAY DIFFRACTIONr_angle_other_deg1.521.61333956
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.16351792
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.05121.458768
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.707152784
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.15415112
X-RAY DIFFRACTIONr_chiral_restr0.070.21908
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0216884
X-RAY DIFFRACTIONr_gen_planes_other0.020.023500
X-RAY DIFFRACTIONr_rigid_bond_restr3.916330064
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A151760.03
12B151760.03
21A151580.03
22C151580.03
31A151740.03
32D151740.03
41B151850.03
42C151850.03
51B151720.04
52D151720.04
61C151650.04
62D151650.04
LS refinement shellResolution: 2.11→2.165 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 423 -
Rwork0.311 7826 -
all-8249 -
obs--97.08 %
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)
10.48090.0107-0.09270.4747-0.15490.3792-0.00860.0265-0.07170.00270.066-0.00630.0398-0.0584-0.05740.0884-0.0267-0.02370.020.00720.030721.423228.998121.918
20.47190.0659-0.01360.41130.24680.34770.01340.0194-0.02940.0330.02380.01520.05130.0016-0.03720.0554-0.0088-0.03230.00430.00740.028518.1961-10.95849.3642
30.52270.16720.06410.39930.1780.4065-0.03080.05770.04720.00590.05450.0256-0.06650.0542-0.02370.0724-0.0203-0.03890.01620.01230.04348.5779-45.364170.8529
40.3875-0.025-0.11260.5422-0.10510.41370.01590.02470.00090.06880.0372-0.0492-0.08690.0142-0.05320.0803-0.0193-0.03230.01360.00430.04040.0339-0.08810.3363
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A35 - 502
2X-RAY DIFFRACTION2B35 - 502
3X-RAY DIFFRACTION3C35 - 502
4X-RAY DIFFRACTION4D35 - 502

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