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- PDB-6ciz: Human Cytochrome P450 17A1 in complex with inhibitor: abiraterone... -

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Basic information

Entry
Database: PDB / ID: 6ciz
TitleHuman Cytochrome P450 17A1 in complex with inhibitor: abiraterone C6 nitrile
ComponentsSteroid 17-alpha-hydroxylase/17,20 lyase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / CYTOCHROME P450 / P450 / CYP17A1 / P450C17 / P450 17A1 / MONOOXYGENASE / 17A-HYDROXYLASE / 17 / 20-LYASE / HEME PROTEIN / CYTOCHROME P450 OXIDOREDUCTASE / MEMBRANE / MICROSOME / ENDOPLASMIC RETICULUM / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


Defective CYP17A1 causes AH5 / steroid 17alpha-monooxygenase / 17alpha-hydroxyprogesterone deacetylase / steroid 17-alpha-monooxygenase activity / glucocorticoid biosynthetic process / Androgen biosynthesis / hormone biosynthetic process / Glucocorticoid biosynthesis / androgen biosynthetic process / sex differentiation ...Defective CYP17A1 causes AH5 / steroid 17alpha-monooxygenase / 17alpha-hydroxyprogesterone deacetylase / steroid 17-alpha-monooxygenase activity / glucocorticoid biosynthetic process / Androgen biosynthesis / hormone biosynthetic process / Glucocorticoid biosynthesis / androgen biosynthetic process / sex differentiation / progesterone metabolic process / steroid biosynthetic process / steroid metabolic process / oxygen binding / lyase activity / iron ion binding / axon / neuronal cell body / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
Cytochrome P450, E-class, group I / 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
6-cyano-17-(3-pyridyl)-androst-5,16-dien-3-ol / PROTOPORPHYRIN IX CONTAINING FE / Steroid 17-alpha-hydroxylase/17,20 lyase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.601 Å
AuthorsScott, E.E. / Fehl, C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM102505 United States
CitationJournal: J. Med. Chem. / Year: 2018
Title: Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2.
Authors: Fehl, C. / Vogt, C.D. / Yadav, R. / Li, K. / Scott, E.E. / Aube, J.
History
DepositionFeb 25, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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: Steroid 17-alpha-hydroxylase/17,20 lyase
B: Steroid 17-alpha-hydroxylase/17,20 lyase
C: Steroid 17-alpha-hydroxylase/17,20 lyase
D: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,92512
Polymers222,9614
Non-polymers3,9648
Water2,504139
1
A: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7313
Polymers55,7401
Non-polymers9912
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7313
Polymers55,7401
Non-polymers9912
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7313
Polymers55,7401
Non-polymers9912
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7313
Polymers55,7401
Non-polymers9912
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.623, 153.351, 168.997
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Steroid 17-alpha-hydroxylase/17,20 lyase / 17-alpha-hydroxyprogesterone aldolase / CYPXVII / Cytochrome P450 17A1 / Cytochrome P450-C17 / ...17-alpha-hydroxyprogesterone aldolase / CYPXVII / Cytochrome P450 17A1 / Cytochrome P450-C17 / Cytochrome P450c17 / Steroid 17-alpha-monooxygenase


Mass: 55740.141 Da / Num. of mol.: 4 / Fragment: residues 24-508
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP17A1, CYP17, S17AH / Production host: Escherichia coli (E. coli)
References: UniProt: P05093, steroid 17alpha-monooxygenase, 17alpha-hydroxyprogesterone deacetylase
#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-3NR / 6-cyano-17-(3-pyridyl)-androst-5,16-dien-3-ol


Mass: 374.519 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C25H30N2O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O

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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: 2.6 Å3/Da / Density % sol: 52.77 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.175 M Tris, pH 8.5 containing 35% PEG 3350, 3% glycerol, and 0.250-0.275 M lithium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.6→39.31 Å / Num. obs: 71754 / % possible obs: 99.3 % / Redundancy: 6.6 % / Rpim(I) all: 0.062 / Net I/σ(I): 10.8
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 6 % / Mean I/σ(I) obs: 1.7 / Num. unique obs: 10016 / Rpim(I) all: 0.53 / % possible all: 96.2

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998)refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SWZ

3swz


Resolution: 2.601→38.338 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.243 3615 5.05 %
Rwork0.1849 --
obs0.1878 71651 99.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.601→38.338 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14992 0 284 139 15415
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00315649
X-RAY DIFFRACTIONf_angle_d0.60521265
X-RAY DIFFRACTIONf_dihedral_angle_d14.4129394
X-RAY DIFFRACTIONf_chiral_restr0.0422384
X-RAY DIFFRACTIONf_plane_restr0.0032682
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6014-2.63560.32471150.27112249X-RAY DIFFRACTION85
2.6356-2.67170.35481150.27522557X-RAY DIFFRACTION100
2.6717-2.70980.34361300.27082641X-RAY DIFFRACTION100
2.7098-2.75030.34591390.27832570X-RAY DIFFRACTION100
2.7503-2.79320.34791510.28352596X-RAY DIFFRACTION100
2.7932-2.8390.38731490.29072579X-RAY DIFFRACTION100
2.839-2.88790.31831540.26062609X-RAY DIFFRACTION100
2.8879-2.94040.29251640.24932552X-RAY DIFFRACTION100
2.9404-2.9970.32951410.23522621X-RAY DIFFRACTION100
2.997-3.05810.30991370.2432603X-RAY DIFFRACTION100
3.0581-3.12460.29671280.22642653X-RAY DIFFRACTION100
3.1246-3.19720.29551400.22122613X-RAY DIFFRACTION100
3.1972-3.27720.29241330.22742576X-RAY DIFFRACTION100
3.2772-3.36570.29581320.22572642X-RAY DIFFRACTION100
3.3657-3.46470.26751360.19572631X-RAY DIFFRACTION100
3.4647-3.57640.28331180.19122660X-RAY DIFFRACTION100
3.5764-3.70420.25531540.18622589X-RAY DIFFRACTION100
3.7042-3.85230.20231450.16442641X-RAY DIFFRACTION100
3.8523-4.02750.2251370.15652624X-RAY DIFFRACTION100
4.0275-4.23960.19681550.14972654X-RAY DIFFRACTION100
4.2396-4.50480.20821330.14772638X-RAY DIFFRACTION100
4.5048-4.8520.16341270.12782662X-RAY DIFFRACTION100
4.852-5.33910.18331510.1422653X-RAY DIFFRACTION99
5.3391-6.1090.21341380.17352676X-RAY DIFFRACTION100
6.109-7.68650.23491320.16982743X-RAY DIFFRACTION100
7.6865-38.34190.20491610.15322804X-RAY DIFFRACTION99

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