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- PDB-7m8v: Human CYP11B2 in complex with LCI699 -

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Basic information

Entry
Database: PDB / ID: 7m8v
TitleHuman CYP11B2 in complex with LCI699
ComponentsCytochrome P450 11B2, mitochondrial
KeywordsOXIDOREDUCTASE / aldosterone synthase / CYP11B2
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, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-YSY / Cytochrome P450 11B2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.08 Å
AuthorsScott, E.E. / Brixius-Anderko, S.
Funding support United States, 1items
OrganizationGrant numberCountry
American Heart Association19POST34430199 United States
CitationJournal: Hypertension / Year: 2021
Title: Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design.
Authors: Brixius-Anderko, S. / Scott, E.E.
History
DepositionMar 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / database_2
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
Revision 1.2Oct 18, 2023Group: 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

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Assembly

Deposited unit
A: Cytochrome P450 11B2, mitochondrial
B: Cytochrome P450 11B2, mitochondrial
C: Cytochrome P450 11B2, mitochondrial
D: Cytochrome P450 11B2, mitochondrial
E: Cytochrome P450 11B2, mitochondrial
F: Cytochrome P450 11B2, mitochondrial
G: Cytochrome P450 11B2, mitochondrial
H: Cytochrome P450 11B2, mitochondrial
I: Cytochrome P450 11B2, mitochondrial
J: Cytochrome P450 11B2, mitochondrial
K: Cytochrome P450 11B2, mitochondrial
L: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)678,50836
Polymers668,38312
Non-polymers10,12524
Water1086
1
A: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
I: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
10
J: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
11
K: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
12
L: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5423
Polymers55,6991
Non-polymers8442
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)123.946, 126.423, 174.928
Angle α, β, γ (deg.)82.807, 70.033, 79.369
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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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: 55698.598 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP11B2 / Plasmid: pCWori+ / Production host: Escherichia coli (E. coli) / Strain (production host): DH5alpha
References: UniProt: P19099, corticosterone 18-monooxygenase, steroid 11beta-monooxygenase
#2: Chemical
ChemComp-YSY / 4-[(4R,5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile / Osilodrostat


Mass: 227.237 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C13H10FN3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, hormone*YM
#3: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: C34H32FeN4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 3.82 Å3/Da / Density % sol: 67.84 % / Description: Plate
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M HEPES (pH 7.5) 4% PEG 8,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.1271 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1271 Å / Relative weight: 1
ReflectionResolution: 3.07→38 Å / Num. obs: 164951 / % possible obs: 92.8 % / Redundancy: 3.7 % / CC1/2: 0.988 / Rpim(I) all: 0.081 / Net I/σ(I): 9.3
Reflection shellResolution: 3.07→3.12 Å / Redundancy: 3.5 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 8467 / CC1/2: 0.549 / Rpim(I) all: 0.62 / % possible all: 95

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
Cootmodel building
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4FDH

4fdh


Resolution: 3.08→37.95 Å / SU ML: 0.3583 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 25.6493
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2419 2005 1.39 %
Rwork0.2018 142189 -
obs0.2023 144194 79.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.64 Å2
Refinement stepCycle: LAST / Resolution: 3.08→37.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms45109 0 720 6 45835
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00447126
X-RAY DIFFRACTIONf_angle_d0.624264102
X-RAY DIFFRACTIONf_chiral_restr0.03736938
X-RAY DIFFRACTIONf_plane_restr0.00388141
X-RAY DIFFRACTIONf_dihedral_angle_d24.545117425
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.08-3.160.3604590.32234043X-RAY DIFFRACTION31.77
3.16-3.240.318900.29016412X-RAY DIFFRACTION50.42
3.24-3.340.31651070.27417644X-RAY DIFFRACTION60.11
3.34-3.450.29741210.25598995X-RAY DIFFRACTION70.66
3.45-3.570.29491540.250110349X-RAY DIFFRACTION81.64
3.57-3.710.28531670.242811806X-RAY DIFFRACTION92.47
3.71-3.880.25811680.21511912X-RAY DIFFRACTION93.78
3.88-4.090.23921700.204811873X-RAY DIFFRACTION93.33
4.09-4.340.21551660.183111768X-RAY DIFFRACTION92.6
4.34-4.680.21361680.171111441X-RAY DIFFRACTION90.04
4.68-5.150.20521420.179611066X-RAY DIFFRACTION86.76
5.15-5.890.20641440.19739888X-RAY DIFFRACTION77.76
5.89-7.410.28251790.211112617X-RAY DIFFRACTION99.19
7.41-37.950.20531700.162112375X-RAY DIFFRACTION97.25

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