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- PDB-6q2t: Human sterol 14a-demethylase (CYP51) in complex with the function... -

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Basic information

Entry
Database: PDB / ID: 6q2t
TitleHuman sterol 14a-demethylase (CYP51) in complex with the functionally irreversible inhibitor (R)-N-(1-(3-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-(3-fluoro-5-(5-fluoropyrimidin-4-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide
ComponentsLanosterol 14-alpha demethylase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / monooxygenase / sterol biosynthesis / cytochrome P450 / structure-based drug design / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


sterol 14alpha-demethylase / sterol 14-demethylase activity / negative regulation of amyloid-beta clearance / sterol metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / steroid biosynthetic process / cholesterol biosynthetic process / negative regulation of protein secretion / Endogenous sterols ...sterol 14alpha-demethylase / sterol 14-demethylase activity / negative regulation of amyloid-beta clearance / sterol metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / steroid biosynthetic process / cholesterol biosynthetic process / negative regulation of protein secretion / Endogenous sterols / Activation of gene expression by SREBF (SREBP) / negative regulation of protein catabolic process / oxidoreductase activity / iron ion binding / heme binding / endoplasmic reticulum membrane / membrane
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
PROTOPORPHYRIN IX CONTAINING FE / Chem-PJM / Lanosterol 14-alpha demethylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsFriggeri, L. / Hargrove, T.Y. / Wawrzak, Z. / Lepesheva, G.I.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01067871 United States
CitationJournal: J.Med.Chem. / Year: 2019
Title: Validation of Human Sterol 14 alpha-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors.
Authors: Friggeri, L. / Hargrove, T.Y. / Wawrzak, Z. / Guengerich, F.P. / Lepesheva, G.I.
History
DepositionAug 8, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lanosterol 14-alpha demethylase
B: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,51315
Polymers102,1052
Non-polymers6,40813
Water52229
1
A: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,16612
Polymers51,0531
Non-polymers5,11311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,3473
Polymers51,0531
Non-polymers1,2952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)117.664, 117.664, 157.842
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number79
Space group name H-MI4

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Components

#1: Protein Lanosterol 14-alpha demethylase / LDM / CYPLI / Cytochrome P450 51A1 / Cytochrome P450-14DM / Cytochrome P45014DM / Cytochrome P450LI ...LDM / CYPLI / Cytochrome P450 51A1 / Cytochrome P450-14DM / Cytochrome P45014DM / Cytochrome P450LI / Sterol 14-alpha demethylase


Mass: 51052.539 Da / Num. of mol.: 2 / Fragment: UNP residues 61-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP51A1, CYP51 / Plasmid: pCW / Production host: Escherichia coli (E. coli) / Strain (production host): HMS174
References: UniProt: Q16850, sterol 14alpha-demethylase, sterol 14alpha-demethylase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-PJM / N-[(1R)-1-(3-chloro-4'-fluoro[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethyl]-4-{5-[3-fluoro-5-(5-fluoropyrimidin-4-yl)phenyl]-1,3,4-oxadiazol-2-yl}benzamide


Mass: 678.062 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C36H23ClF3N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-DXC / (3ALPHA,5BETA,12ALPHA)-3,12-DIHYDROXYCHOLAN-24-OIC ACID / DEOXYCHOLIC ACID / Deoxycholic acid


Mass: 392.572 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C24H40O4 / Comment: detergent*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 2.68 Å3/Da / Density % sol: 54.02 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 15 mM sodium cholate, 8% PEG3350, 0.2 M potassium formate, pH 7.4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 19, 2019
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.8→94.35 Å / Num. obs: 26405 / % possible obs: 99.6 % / Redundancy: 5.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.046 / Net I/σ(I): 12.3
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.996 / Num. unique obs: 1871 / CC1/2: 0.853 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4UHI

4uhi


Resolution: 2.8→28.098 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.937 / SU B: 23.112 / SU ML: 0.417 / Cross valid method: THROUGHOUT / ESU R Free: 0.403
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2559 1258 4.785 %
Rwork0.2268 --
all0.228 --
obs-26289 99.561 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.581 Å2-0 Å2-0 Å2
2--1.581 Å2-0 Å2
3----3.162 Å2
Refinement stepCycle: LAST / Resolution: 2.8→28.098 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7172 0 457 29 7658
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0147871
X-RAY DIFFRACTIONr_bond_other_d0.0020.0187284
X-RAY DIFFRACTIONr_angle_refined_deg1.1661.74110757
X-RAY DIFFRACTIONr_angle_other_deg1.1341.67616933
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1655887
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.61121.744390
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.007151280
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0191550
X-RAY DIFFRACTIONr_chiral_restr0.0410.21023
X-RAY DIFFRACTIONr_chiral_restr_other1.2320.2107
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.028483
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021699
X-RAY DIFFRACTIONr_nbd_refined0.2390.21933
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2580.27508
X-RAY DIFFRACTIONr_nbtor_refined0.1780.23861
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.23133
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1760.2200
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0830.26
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2980.220
X-RAY DIFFRACTIONr_nbd_other0.3510.2112
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2750.23
X-RAY DIFFRACTIONr_mcbond_it7.34810.0683554
X-RAY DIFFRACTIONr_mcbond_other7.34210.0673553
X-RAY DIFFRACTIONr_mcangle_it11.12915.094439
X-RAY DIFFRACTIONr_mcangle_other11.12915.0924440
X-RAY DIFFRACTIONr_scbond_it6.92310.4144316
X-RAY DIFFRACTIONr_scbond_other6.92210.4134317
X-RAY DIFFRACTIONr_scangle_it10.79215.3666318
X-RAY DIFFRACTIONr_scangle_other10.79115.3656319
X-RAY DIFFRACTIONr_lrange_it15.389117.9919179
X-RAY DIFFRACTIONr_lrange_other15.388117.9859180
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.8730.387770.3741871X-RAY DIFFRACTION99.9487
2.873-2.9520.365840.3751811X-RAY DIFFRACTION99.8946
2.952-3.0370.38830.3551737X-RAY DIFFRACTION99.8902
3.037-3.130.392940.3411695X-RAY DIFFRACTION99.9441
3.13-3.2330.323790.3221657X-RAY DIFFRACTION99.9424
3.233-3.3460.345720.2971604X-RAY DIFFRACTION99.9404
3.346-3.4720.328680.2771586X-RAY DIFFRACTION99.819
3.472-3.6140.32550.2621481X-RAY DIFFRACTION99.7403
3.614-3.7740.314840.2631381X-RAY DIFFRACTION99.6599
3.774-3.9580.306840.2451387X-RAY DIFFRACTION99.6612
3.958-4.1720.24920.2241238X-RAY DIFFRACTION99.5509
4.172-4.4250.219740.211213X-RAY DIFFRACTION99.536
4.425-4.7290.258610.1881147X-RAY DIFFRACTION99.67
4.729-5.1070.264400.1951087X-RAY DIFFRACTION99.4704
5.107-5.5930.237650.193978X-RAY DIFFRACTION99.618
5.593-6.2510.23450.204887X-RAY DIFFRACTION99.3603
6.251-7.2120.176370.194802X-RAY DIFFRACTION99.1726
7.212-8.820.128390.156675X-RAY DIFFRACTION99.1667
8.82-12.420.165180.143521X-RAY DIFFRACTION98.7179
12.42-280.2970.231273X-RAY DIFFRACTION87.7743

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