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- PDB-6wr1: Human steroidogenic cytochrome P450 17A1 mutant N52Y with inhibit... -

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Basic information

Entry
Database: PDB / ID: 6wr1
TitleHuman steroidogenic cytochrome P450 17A1 mutant N52Y with inhibitor abiraterone
ComponentsSteroid 17-alpha-hydroxylase/17,20 lyase
KeywordsOXIDOREDUCTASE / Cytochrome P450 / P450 / 17A1
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, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
Abiraterone / 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: 1.85 Å
AuthorsPetrunak, E.M. / Bart, A.G. / Scott, E.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM102505 United States
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Human cytochrome P450 17A1 structures with metabolites of prostate cancer drug abiraterone reveal substrate-binding plasticity and a second binding site.
Authors: Petrunak, E.M. / Bart, A.G. / Peng, H.M. / Auchus, R.J. / Scott, E.E.
History
DepositionApr 29, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2023Group: Database references / Refinement description
Category: citation / citation_author ...citation / citation_author / database_2 / struct_ncs_dom_lim
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,5106
Polymers111,5782
Non-polymers1,9324
Water8,899494
1
A: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7553
Polymers55,7891
Non-polymers9662
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)56,7553
Polymers55,7891
Non-polymers9662
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.056, 105.004, 108.544
Angle α, β, γ (deg.)90.000, 101.023, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSLYSLYS(chain 'A' and (resid 29 through 136 or resid 142 through 501 or resid 600 through 601))AA29 - 13611 - 118
12LEULEUSERSER(chain 'A' and (resid 29 through 136 or resid 142 through 501 or resid 600 through 601))AA142 - 273124 - 255
13ASPASPGLUGLU(chain 'A' and (resid 29 through 136 or resid 142 through 501 or resid 600 through 601))AA283 - 501265 - 483
14HEMHEMAERAER(chain 'A' and (resid 29 through 136 or resid 142 through 501 or resid 600 through 601))AC - D600 - 601
25LYSLYSPHEPHE(chain 'B' and (resid 29 through 274 or resid 284 through 501 or resid 600 through 601))BB29 - 13511 - 117
26LYSLYSASPASP(chain 'B' and (resid 29 through 274 or resid 284 through 501 or resid 600 through 601))BB141 - 274123 - 256
27SERSERGLUGLU(chain 'B' and (resid 29 through 274 or resid 284 through 501 or resid 600 through 601))BB284 - 501266 - 483
28HEMHEMAERAER(chain 'B' and (resid 29 through 274 or resid 284 through 501 or resid 600 through 601))BE - F600 - 601

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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: 55789.211 Da / Num. of mol.: 2 / Mutation: N52Y
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.: 2 / Source method: isolated from a natural source / Formula: C34H32FeN4O4
#3: Chemical ChemComp-AER / Abiraterone / (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol


Mass: 349.509 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H31NO / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 494 / 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: 2.5 Å3/Da / Density % sol: 50.81 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 100 mM Tris HCl, pH 8.5, 30% PEG 3350, 250 mM Li2SO4, 3% glycerol, covered with Al's oil

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 28, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.85→39.23 Å / Num. obs: 88757 / % possible obs: 98.3 % / Redundancy: 6.4 % / Biso Wilson estimate: 30.25 Å2 / Rpim(I) all: 0.03 / Net I/σ(I): 14.1
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 6.4 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 12773 / Rpim(I) all: 0.465 / % possible all: 97.4

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Unpublished 17A1 model

17a1


Resolution: 1.85→39.23 Å / SU ML: 0.2278 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.3461
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2179 4450 5.02 %
Rwork0.1897 84134 -
obs0.1911 88584 98.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.5 Å2
Refinement stepCycle: LAST / Resolution: 1.85→39.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7436 0 138 494 8068
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01027760
X-RAY DIFFRACTIONf_angle_d1.012610543
X-RAY DIFFRACTIONf_chiral_restr0.06641185
X-RAY DIFFRACTIONf_plane_restr0.00661318
X-RAY DIFFRACTIONf_dihedral_angle_d16.622871
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.870.35251490.34042542X-RAY DIFFRACTION90.85
1.87-1.890.36271510.30722797X-RAY DIFFRACTION98.53
1.89-1.910.33391490.30552805X-RAY DIFFRACTION98.04
1.91-1.940.31461580.2882778X-RAY DIFFRACTION98.03
1.94-1.960.31031330.2752814X-RAY DIFFRACTION98.96
1.96-1.990.30511430.25622844X-RAY DIFFRACTION98.81
1.99-2.020.26551460.25942802X-RAY DIFFRACTION98.37
2.02-2.050.26151520.24422765X-RAY DIFFRACTION98.18
2.05-2.080.27721610.24582804X-RAY DIFFRACTION97.37
2.08-2.120.2941520.22832765X-RAY DIFFRACTION98.08
2.12-2.150.26291430.23642782X-RAY DIFFRACTION97.21
2.15-2.190.28671400.22432747X-RAY DIFFRACTION95.53
2.19-2.230.24661460.21572808X-RAY DIFFRACTION99.13
2.23-2.280.25831490.20642821X-RAY DIFFRACTION98.84
2.28-2.330.21911360.19492825X-RAY DIFFRACTION99.06
2.33-2.380.21581450.19832855X-RAY DIFFRACTION99.08
2.38-2.440.21931590.20342818X-RAY DIFFRACTION99.07
2.44-2.510.27871610.20562846X-RAY DIFFRACTION99.24
2.51-2.580.22741470.19742803X-RAY DIFFRACTION98.76
2.58-2.670.22721460.20252823X-RAY DIFFRACTION98.18
2.67-2.760.20571490.20382774X-RAY DIFFRACTION97.69
2.76-2.870.21571370.19052746X-RAY DIFFRACTION95.75
2.87-30.28851400.22871X-RAY DIFFRACTION99.18
3-3.160.22191450.20032840X-RAY DIFFRACTION99.3
3.16-3.360.23981450.18892836X-RAY DIFFRACTION99.3
3.36-3.620.21831500.17972879X-RAY DIFFRACTION99.74
3.62-3.980.16811400.15682827X-RAY DIFFRACTION97.7
3.98-4.560.15491340.14312806X-RAY DIFFRACTION97.58
4.56-5.740.16831740.14632848X-RAY DIFFRACTION99.54
5.74-39.230.18831700.16952863X-RAY DIFFRACTION97.78

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