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

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Basic information

Entry
Database: PDB / ID: 6chi
TitleHuman Cytochrome P450 17A1 in complex with inhibitor: abiraterone C6 amide
ComponentsSteroid 17-alpha-hydroxylase/17,20 lyase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / CYTOCHROME P450 / P450 / CYP17A1 / P450C17 / P450 17A1 / MONOOXYGENASE / 17A-HYDROXYLASE / 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 / estrogen 16-alpha-hydroxylase activity / 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
Chem-3NX / 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: 2.698 Å
AuthorsScott, E.E.
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 22, 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_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.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)226,99712
Polymers222,9614
Non-polymers4,0368
Water1,54986
1
A: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7493
Polymers55,7401
Non-polymers1,0092
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)56,7493
Polymers55,7401
Non-polymers1,0092
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)56,7493
Polymers55,7401
Non-polymers1,0092
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)56,7493
Polymers55,7401
Non-polymers1,0092
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.424, 154.108, 167.891
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: isolated from a natural source / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-3NX / 3-hydroxy-17-(3-pyridyl)-androst-5,16-dien-6-amide


Mass: 392.534 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H32N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.59 Å3/Da / Density % sol: 52.59 %
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: 2.698→38.673 Å / Num. obs: 64275 / % possible obs: 99.5 % / Redundancy: 6.6 % / Rpim(I) all: 0.054 / Net I/σ(I): 14.6
Reflection shellResolution: 2.698→2.84 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 1.6 / Num. unique obs: 9066 / Rpim(I) all: 0.536 / % possible all: 97.6

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155:0000)refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SWZ

3swz


Resolution: 2.698→38.673 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.242 3244 5.06 %
Rwork0.1868 --
obs0.1895 64151 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.698→38.673 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14944 0 288 86 15318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00315604
X-RAY DIFFRACTIONf_angle_d0.56221210
X-RAY DIFFRACTIONf_dihedral_angle_d12.8419376
X-RAY DIFFRACTIONf_chiral_restr0.0412380
X-RAY DIFFRACTIONf_plane_restr0.0022676
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6983-2.73860.38621170.30382377X-RAY DIFFRACTION91
2.7386-2.78140.35461490.27542635X-RAY DIFFRACTION100
2.7814-2.8270.31871210.2622622X-RAY DIFFRACTION100
2.827-2.87570.31081440.25682622X-RAY DIFFRACTION100
2.8757-2.9280.34931360.26872624X-RAY DIFFRACTION100
2.928-2.98430.3721260.28082657X-RAY DIFFRACTION100
2.9843-3.04510.36831520.27212582X-RAY DIFFRACTION100
3.0451-3.11130.35511220.25352662X-RAY DIFFRACTION100
3.1113-3.18370.3191410.23472663X-RAY DIFFRACTION100
3.1837-3.26330.28481240.22572636X-RAY DIFFRACTION100
3.2633-3.35140.30651410.22642649X-RAY DIFFRACTION100
3.3514-3.450.25351240.21152676X-RAY DIFFRACTION100
3.45-3.56130.2611560.21282629X-RAY DIFFRACTION100
3.5613-3.68850.25841560.19932614X-RAY DIFFRACTION100
3.6885-3.8360.23861430.18172647X-RAY DIFFRACTION100
3.836-4.01040.23591420.16832661X-RAY DIFFRACTION100
4.0104-4.22160.21461380.15572683X-RAY DIFFRACTION100
4.2216-4.48580.23331580.15062631X-RAY DIFFRACTION100
4.4858-4.83150.19591560.13392667X-RAY DIFFRACTION100
4.8315-5.31660.17911640.14782683X-RAY DIFFRACTION100
5.3166-6.08340.19541310.17682706X-RAY DIFFRACTION100
6.0834-7.65460.23411400.17112756X-RAY DIFFRACTION100
7.6546-38.67670.16941630.14772825X-RAY DIFFRACTION99

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