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- PDB-6xz8: Structure of aldosterone synthase (CYP11B2) in complex with N-[(1... -

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Basic information

Entry
Database: PDB / ID: 6xz8
TitleStructure of aldosterone synthase (CYP11B2) in complex with N-[(1R)-1-[5-(6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]ethyl]methanesulfonamide
ComponentsCytochrome P450 11B2, mitochondrial
KeywordsOXIDOREDUCTASE / CYTOCHROME P450 / CYP11B2 / ALDOSTERONE SYNTHASE
Function / homology
Function and homology information


corticosterone 18-monooxygenase / regulation of blood volume by renal aldosterone / Defective CYP11B2 causes CMO-1 deficiency / mineralocorticoid biosynthetic process / steroid 11beta-monooxygenase / steroid 11-beta-monooxygenase activity / corticosterone 18-monooxygenase activity / cortisol metabolic process / aldosterone biosynthetic process / cortisol biosynthetic process ...corticosterone 18-monooxygenase / regulation of blood volume by renal aldosterone / Defective CYP11B2 causes CMO-1 deficiency / mineralocorticoid biosynthetic process / steroid 11beta-monooxygenase / steroid 11-beta-monooxygenase activity / corticosterone 18-monooxygenase activity / cortisol metabolic process / aldosterone biosynthetic process / cortisol biosynthetic process / Mineralocorticoid biosynthesis / glucocorticoid biosynthetic process / Glucocorticoid biosynthesis / sodium ion homeostasis / sterol metabolic process / cellular response to potassium ion / C21-steroid hormone biosynthetic process / potassium ion homeostasis / renal water homeostasis / steroid hydroxylase activity / cellular response to peptide hormone stimulus / Endogenous sterols / cellular response to hormone stimulus / cholesterol metabolic process / mitochondrial inner membrane / iron ion binding / heme binding / mitochondrion
Similarity search - Function
Cytochrome P450, mitochondrial / 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
HEME C / Chem-O4T / Cytochrome P450 11B2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsKuglstatter, A. / Joseph, C. / Benz, J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors.
Authors: Liu, Y. / Wu, J. / Zhou, M. / Chen, W. / Li, D. / Wang, Z. / Hornsperger, B. / Aebi, J.D. / Marki, H.P. / Kuhn, B. / Wang, L. / Kuglstatter, A. / Benz, J. / Muller, S. / Hochstrasser, R. / ...Authors: Liu, Y. / Wu, J. / Zhou, M. / Chen, W. / Li, D. / Wang, Z. / Hornsperger, B. / Aebi, J.D. / Marki, H.P. / Kuhn, B. / Wang, L. / Kuglstatter, A. / Benz, J. / Muller, S. / Hochstrasser, R. / Ottaviani, G. / Xin, J. / Kirchner, S. / Mohr, S. / Verry, P. / Riboulet, W. / Shen, H.C. / Mayweg, A.V. / Amrein, K. / Tan, X.
History
DepositionFeb 3, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2May 1, 2024Group: 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: Cytochrome P450 11B2, mitochondrial
B: Cytochrome P450 11B2, mitochondrial
C: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,7649
Polymers168,7273
Non-polymers3,0376
Water1,11762
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8050 Å2
ΔGint-76 kcal/mol
Surface area54940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.323, 121.730, 298.559
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Cytochrome P450 11B2, mitochondrial / Aldosterone synthase / ALDOS / Aldosterone-synthesizing enzyme / CYPXIB2 / Corticosterone 18- ...Aldosterone synthase / ALDOS / Aldosterone-synthesizing enzyme / CYPXIB2 / Corticosterone 18-monooxygenase / CYP11B2 / Cytochrome P-450Aldo / Cytochrome P-450C18 / Steroid 11-beta-hydroxylase / Steroid 18-hydroxylase


Mass: 56242.199 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP11B2 / Production host: Escherichia coli (E. coli)
References: UniProt: P19099, corticosterone 18-monooxygenase, steroid 11beta-monooxygenase
#2: Chemical ChemComp-HEC / HEME C / Heme C


Mass: 618.503 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H34FeN4O4
#3: Chemical ChemComp-O4T / ~{N}-[(1~{R})-1-[5-(6-chloranyl-1,1-dimethyl-3-oxidanylidene-isoindol-2-yl)pyridin-3-yl]ethyl]methanesulfonamide


Mass: 393.888 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H20ClN3O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 62 / 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: 2.89 Å3/Da / Density % sol: 57.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 10% PEG3350, 0.09M ammonium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 9, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→47.17 Å / Num. obs: 39576 / % possible obs: 99.9 % / Redundancy: 6.7 % / Biso Wilson estimate: 80.08 Å2 / Rmerge(I) obs: 0.249 / Rsym value: 0.249 / Net I/σ(I): 6.48
Reflection shellResolution: 3→3.16 Å / Redundancy: 6.8 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 5710 / Rpim(I) all: 0.654 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished in-house structure

Resolution: 3→47.17 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.872 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.349
RfactorNum. reflection% reflectionSelection details
Rfree0.221 1983 5.02 %RANDOM
Rwork0.189 ---
obs0.191 39522 99.8 %-
Displacement parametersBiso max: 155.94 Å2 / Biso mean: 65.57 Å2 / Biso min: 23.02 Å2
Baniso -1Baniso -2Baniso -3
1-20.1275 Å20 Å20 Å2
2---22.7256 Å20 Å2
3---2.598 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: final / Resolution: 3→47.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11391 0 207 62 11660
Biso mean--53.19 40.13 -
Num. residues----1404
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4075SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2006HARMONIC5
X-RAY DIFFRACTIONt_it11927HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1446SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13755SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d11927HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg16242HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.39
X-RAY DIFFRACTIONt_other_torsion20.68
LS refinement shellResolution: 3→3.02 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2703 47 5.94 %
Rwork0.2673 744 -
all-791 -
obs--99.63 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.6493-0.0618-0.43440.43850.17461.4948-0.0138-0.17280.02770.0363-0.0261-0.0705-0.01670.10260.03990.0238-0.02270.0064-0.04650.1190.0867-8.295230.50772.1081
21.4967-0.23710.05040.67180.00721.69620.08080.13480.0427-0.051-0.06980.0431-0.2051-0.143-0.0110.06630.0153-0.0241-0.0673-0.02930.0741-30.582134.861623.6356
31.98180.1420.35220.6191-0.08781.6502-0.07090.2512-0.1431-0.07640.10130.0279-0.05010.3008-0.03040.09050.02390.002-0.0261-0.03820.126321.450824.686327.9624
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|34 - A|503 D|1 L|1 }A34 - 503
2X-RAY DIFFRACTION1{ A|34 - A|503 D|1 L|1 }D1
3X-RAY DIFFRACTION1{ A|34 - A|503 D|1 L|1 }L1
4X-RAY DIFFRACTION2{ B|32 - B|504 D|2 L|2 }B32 - 504
5X-RAY DIFFRACTION2{ B|32 - B|504 D|2 L|2 }D2
6X-RAY DIFFRACTION2{ B|32 - B|504 D|2 L|2 }L2
7X-RAY DIFFRACTION3{ C|34 - C|503 D|3 L|3 }C34 - 503
8X-RAY DIFFRACTION3{ C|34 - C|503 D|3 L|3 }D3
9X-RAY DIFFRACTION3{ C|34 - C|503 D|3 L|3 }L3

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