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- PDB-6xz9: Structure of aldosterone synthase (CYP11B2) in complex with 5-chl... -

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Basic information

Entry
Database: PDB / ID: 6xz9
TitleStructure of aldosterone synthase (CYP11B2) in complex with 5-chloro-3,3-dimethyl-2-[5-[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxy-3-pyridyl]isoindolin-1-one
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 / steroid 11beta-monooxygenase / steroid 11-beta-monooxygenase activity / mineralocorticoid biosynthetic process / 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 / steroid 11beta-monooxygenase / steroid 11-beta-monooxygenase activity / mineralocorticoid biosynthetic process / 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 / steroid hydroxylase activity / cellular response to peptide hormone stimulus / Endogenous sterols / renal water homeostasis / 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-O4W / Cytochrome P450 11B2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.77 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)171,9389
Polymers168,7273
Non-polymers3,2116
Water2,396133
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8130 Å2
ΔGint-67 kcal/mol
Surface area54980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.682, 121.603, 298.702
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


Mass: 618.503 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H34FeN4O4
#3: Chemical ChemComp-O4W / 5-chloranyl-3,3-dimethyl-2-[5-[1-(1-methylpyrazol-4-yl)carbonylazetidin-3-yl]oxypyridin-3-yl]isoindol-1-one


Mass: 451.905 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H22ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.9 Å3/Da / Density % sol: 57.55 %
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: Sep 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.77→48.58 Å / Num. obs: 50197 / % possible obs: 99.8 % / Redundancy: 6.64 % / Biso Wilson estimate: 70.22 Å2 / Rmerge(I) obs: 0.296 / Rsym value: 0.296 / Net I/σ(I): 5.5
Reflection shellResolution: 2.77→2.86 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 0.94 / Num. unique obs: 4557 / Rpim(I) all: 0.97 / % possible all: 99.9

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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: 2.77→48.58 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.835 / SU R Cruickshank DPI: 1.265 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.094 / SU Rfree Blow DPI: 0.356 / SU Rfree Cruickshank DPI: 0.366
RfactorNum. reflection% reflectionSelection details
Rfree0.273 2539 5.07 %RANDOM
Rwork0.234 ---
obs0.236 50038 99.5 %-
Displacement parametersBiso max: 135.12 Å2 / Biso mean: 52.15 Å2 / Biso min: 10.24 Å2
Baniso -1Baniso -2Baniso -3
1-2.4742 Å20 Å20 Å2
2---2.1561 Å20 Å2
3----0.3182 Å2
Refine analyzeLuzzati coordinate error obs: 0.48 Å
Refinement stepCycle: final / Resolution: 2.77→48.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11383 0 225 133 11741
Biso mean--45.52 31.15 -
Num. residues----1403
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4072SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2011HARMONIC5
X-RAY DIFFRACTIONt_it11943HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1441SEMIHARMONIC5
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_contact13604SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d11943HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg16264HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.44
X-RAY DIFFRACTIONt_other_torsion20.7
LS refinement shellResolution: 2.77→2.79 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2807 45 4.5 %
Rwork0.2257 956 -
all-1001 -
obs--98.12 %
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)
11.45940.03110.46680.2232-0.14531.28210.0069-0.19760.00770.02660.01360.0684-0.0092-0.1082-0.02060.0187-0.0234-0.00490.2022-0.1160.01488.038730.387471.6984
21.4862-0.3732-0.06181.15470.05411.35410.1140.0364-0.01510.0122-0.0834-0.03890.06280.1222-0.0305-0.0708-0.01290.00950.16470.0061-0.014430.594825.920623.6453
31.41970.0498-0.19410.44490.20171.3121-0.02450.17830.1828-0.03180.08740.043-0.0003-0.264-0.0629-0.02020.02680.00560.16370.04120.0442-21.18536.212928.2798
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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