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

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Basic information

Entry
Database: PDB / ID: 6cir
TitleHuman Cytochrome P450 17A1 in complex with inhibitor: abiraterone C6 oxime
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-oxime-17-(3-pyridyl)-androst-16-en-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: 2.648 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.pdbx_value_order / _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)226,94912
Polymers222,9614
Non-polymers3,9888
Water2,396133
1
A: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7373
Polymers55,7401
Non-polymers9972
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)56,7373
Polymers55,7401
Non-polymers9972
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)56,7373
Polymers55,7401
Non-polymers9972
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)56,7373
Polymers55,7401
Non-polymers9972
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.904, 151.874, 168.188
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-3NQ / 6-oxime-17-(3-pyridyl)-androst-16-en-3-ol


Mass: 380.523 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H32N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.63 Å3/Da / Density % sol: 53.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.175 M Tris, pH 8.5 containing 30% 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: 2.648→39.314 Å / Num. obs: 68518 / % possible obs: 99 % / Redundancy: 6.7 % / Rpim(I) all: 0.061 / Net I/σ(I): 13.1
Reflection shellResolution: 2.65→2.79 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 1.6 / Num. unique obs: 9510 / Rpim(I) all: 0.552 / % possible all: 95.4

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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: 2.648→39.314 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2405 3463 5.06 %
Rwork0.187 --
obs0.1897 68391 98.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.648→39.314 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14931 0 284 133 15348
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00215580
X-RAY DIFFRACTIONf_angle_d0.57221176
X-RAY DIFFRACTIONf_dihedral_angle_d14.0929340
X-RAY DIFFRACTIONf_chiral_restr0.0412380
X-RAY DIFFRACTIONf_plane_restr0.0032667
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6483-2.68450.35381230.31052117X-RAY DIFFRACTION82
2.6845-2.72290.38561360.28132585X-RAY DIFFRACTION100
2.7229-2.76350.38251310.27092593X-RAY DIFFRACTION100
2.7635-2.80670.31891620.26432590X-RAY DIFFRACTION100
2.8067-2.85270.34861400.25632544X-RAY DIFFRACTION100
2.8527-2.90190.35581490.24962593X-RAY DIFFRACTION100
2.9019-2.95460.29871320.23872605X-RAY DIFFRACTION100
2.9546-3.01140.33411300.23522573X-RAY DIFFRACTION99
3.0114-3.07290.27621210.23252571X-RAY DIFFRACTION98
3.0729-3.13960.2771410.22712579X-RAY DIFFRACTION99
3.1396-3.21260.28911420.22472585X-RAY DIFFRACTION100
3.2126-3.2930.30161370.22672629X-RAY DIFFRACTION100
3.293-3.38190.28421380.20342593X-RAY DIFFRACTION100
3.3819-3.48140.2991500.18952604X-RAY DIFFRACTION100
3.4814-3.59370.24581330.19162609X-RAY DIFFRACTION100
3.5937-3.7220.23121640.17372599X-RAY DIFFRACTION100
3.722-3.87090.23791260.16172623X-RAY DIFFRACTION100
3.8709-4.04690.19271270.15582614X-RAY DIFFRACTION98
4.0469-4.26010.19881480.15992606X-RAY DIFFRACTION100
4.2601-4.52660.17331290.14942665X-RAY DIFFRACTION100
4.5266-4.87550.18251440.13922632X-RAY DIFFRACTION100
4.8755-5.36510.20311450.15632655X-RAY DIFFRACTION100
5.3651-6.13890.22651370.1962670X-RAY DIFFRACTION99
6.1389-7.72470.22831330.19442706X-RAY DIFFRACTION100
7.7247-39.31850.19331450.16392788X-RAY DIFFRACTION98

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