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- PDB-5irv: Human cytochrome P450 17A1 bound to inhibitor VT-464 -

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Basic information

Entry
Database: PDB / ID: 5irv
TitleHuman cytochrome P450 17A1 bound to inhibitor VT-464
ComponentsSteroid 17-alpha-hydroxylase/17,20 lyase
KeywordsOXIDOREDUCTASE / LYASE/INHIBITOR / Inhibitor complex / LYASE-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
VT-464 / PROTOPORPHYRIN IX CONTAINING FE / Steroid 17-alpha-hydroxylase/17,20 lyase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.098 Å
AuthorsScott, E.E. / Petrunak, E.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM102505 United States
CitationJournal: Drug Metab. Dispos. / Year: 2017
Title: Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1.
Authors: Petrunak, E.M. / Rogers, S.A. / Aube, J. / Scott, E.E.
History
DepositionMar 14, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 19, 2017Group: Database references
Revision 1.2May 17, 2017Group: Database references
Revision 1.3Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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

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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)227,02412
Polymers222,9614
Non-polymers4,0638
Water00
1
A: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7563
Polymers55,7401
Non-polymers1,0162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7563
Polymers55,7401
Non-polymers1,0162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7563
Polymers55,7401
Non-polymers1,0162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Steroid 17-alpha-hydroxylase/17,20 lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7563
Polymers55,7401
Non-polymers1,0162
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.954, 153.499, 169.035
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and ((resid 36 and (name N or name...
21(chain B and ((resid 36 and (name N or name...
31(chain C and ((resid 36 and (name O or name...
41(chain D and ((resid 36 and (name O or name...

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
11LEULEULEULEU(chain A and ((resid 36 and (name N or name...AA3618
12LEULEUHEMHEM(chain A and ((resid 36 and (name N or name...AA - E31 - 60013
13LEULEUHEMHEM(chain A and ((resid 36 and (name N or name...AA - E31 - 60013
14LEULEUHEMHEM(chain A and ((resid 36 and (name N or name...AA - E31 - 60013
15LEULEUHEMHEM(chain A and ((resid 36 and (name N or name...AA - E31 - 60013
21LEULEULEULEU(chain B and ((resid 36 and (name N or name...BB3618
22LEULEUHEMHEM(chain B and ((resid 36 and (name N or name...BB - G31 - 60013
23LEULEUHEMHEM(chain B and ((resid 36 and (name N or name...BB - G31 - 60013
24LEULEUHEMHEM(chain B and ((resid 36 and (name N or name...BB - G31 - 60013
25LEULEUHEMHEM(chain B and ((resid 36 and (name N or name...BB - G31 - 60013
31LEULEULEULEU(chain C and ((resid 36 and (name O or name...CC3618
32SERSERHEMHEM(chain C and ((resid 36 and (name O or name...CC - I30 - 60012
33SERSERHEMHEM(chain C and ((resid 36 and (name O or name...CC - I30 - 60012
34SERSERHEMHEM(chain C and ((resid 36 and (name O or name...CC - I30 - 60012
35SERSERHEMHEM(chain C and ((resid 36 and (name O or name...CC - I30 - 60012
41LEULEULEULEU(chain D and ((resid 36 and (name O or name...DD3618
42SERSERHEMHEM(chain D and ((resid 36 and (name O or name...DD - K30 - 60012
43SERSERHEMHEM(chain D and ((resid 36 and (name O or name...DD - K30 - 60012
44SERSERHEMHEM(chain D and ((resid 36 and (name O or name...DD - K30 - 60012
45SERSERHEMHEM(chain D and ((resid 36 and (name O or name...DD - K30 - 60012

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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: UNP 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, EC: 4.1.2.30
#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-6D8 / VT-464 / (1S)-1-[6,7-bis(difluoromethoxy)naphthalen-2-yl]-2-methyl-1-(2H-1,2,3-triazol-4-yl)propan-1-ol


Mass: 399.339 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H17F4N3O3

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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: 2.65 Å3/Da / Density % sol: 58.26 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 100 mM sodium cacodylate trihydrate, pH 6.5, 200 mM ammonium sulfate, 30% w/v PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: May 22, 2015
RadiationMonochromator: Liquid nitrogen-cooled double crystal, non-fixed-exit slit
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.098→39.441 Å / Num. all: 43069 / Num. obs: 43069 / % possible obs: 98.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 66.71 Å2 / Rpim(I) all: 0.087 / Rrim(I) all: 0.163 / Rsym value: 0.137 / Net I/av σ(I): 5.2 / Net I/σ(I): 8.4 / Num. measured all: 142288
Reflection shellResolution: 3.1→3.27 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 0.8 / % possible all: 96.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3SWZ

3swz


Resolution: 3.098→39.441 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.11
RfactorNum. reflection% reflectionSelection details
Rfree0.248 2160 5.03 %5
Rwork0.1951 ---
obs0.1978 42930 98.04 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 163.65 Å2 / Biso mean: 68.3109 Å2 / Biso min: 18.39 Å2
Refinement stepCycle: final / Resolution: 3.098→39.441 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15025 0 472 0 15497
Biso mean--51.07 --
Num. residues----1889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00415674
X-RAY DIFFRACTIONf_angle_d0.8121290
X-RAY DIFFRACTIONf_chiral_restr0.0482368
X-RAY DIFFRACTIONf_plane_restr0.0062695
X-RAY DIFFRACTIONf_dihedral_angle_d14.6719366
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A10725X-RAY DIFFRACTION6.681TORSIONAL
12B10725X-RAY DIFFRACTION6.681TORSIONAL
13C10725X-RAY DIFFRACTION6.681TORSIONAL
14D10725X-RAY DIFFRACTION6.681TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.0975-3.16950.38871470.32812486263392
3.1695-3.24880.32851570.28992686284398
3.2488-3.33660.31151280.26152644277298
3.3366-3.43470.27581470.25332719286699
3.4347-3.54550.33611300.25052728285899
3.5455-3.67210.30761330.24042731286499
3.6721-3.8190.27641620.21482717287999
3.819-3.99270.24981500.19582681283198
3.9927-4.2030.26131330.182702283598
4.203-4.46590.24551520.18127562908100
4.4659-4.81020.221550.15472755291099
4.8102-5.29330.23181350.15272728286398
5.2933-6.05680.2321530.18032762291599
6.0568-7.62190.20111310.18342811294299
7.6219-39.44410.18231470.15642864301197

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