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- PDB-4zgx: Structure of aldosterone synthase (CYP11B2) in complex with (+)-(... -

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Entry
Database: PDB / ID: 4zgx
TitleStructure of aldosterone synthase (CYP11B2) in complex with (+)-(R)-N-(4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide
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 / steroid hydroxylase activity / renal water homeostasis / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-QHC / Cytochrome P450 11B2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsKuglstatter, A. / Joseph, C.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.
Authors: Martin, R.E. / Aebi, J.D. / Hornsperger, B. / Krebs, H.J. / Kuhn, B. / Kuglstatter, A. / Alker, A.M. / Marki, H.P. / Muller, S. / Burger, D. / Ottaviani, G. / Riboulet, W. / Verry, P. / Tan, ...Authors: Martin, R.E. / Aebi, J.D. / Hornsperger, B. / Krebs, H.J. / Kuhn, B. / Kuglstatter, A. / Alker, A.M. / Marki, H.P. / Muller, S. / Burger, D. / Ottaviani, G. / Riboulet, W. / Verry, P. / Tan, X. / Amrein, K. / Mayweg, A.V.
History
DepositionApr 24, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 7, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: Database references

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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
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)685,63234
Polymers674,90612
Non-polymers10,72622
Water14,718817
1
A: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8592
Polymers56,2421
Non-polymers6161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8592
Polymers56,2421
Non-polymers6161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
I: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
10
J: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
11
K: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
12
L: Cytochrome P450 11B2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1913
Polymers56,2421
Non-polymers9492
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.700, 125.960, 155.230
Angle α, β, γ (deg.)70.25, 85.87, 73.84
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 56242.199 Da / Num. of mol.: 12 / Fragment: UNP residues 24-503
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, steroid 11beta-monooxygenase, corticosterone 18-monooxygenase
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-QHC / N-[(8R)-4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl]propanamide


Mass: 332.800 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C18H18ClFN2O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 817 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.77 Å3/Da / Density % sol: 55.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: ammonium acetate, bis-tris, PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→88.2 Å / Num. obs: 115062 / % possible obs: 97.3 % / Redundancy: 2.4 % / Biso Wilson estimate: 83.39 Å2 / Rmerge(I) obs: 0.137 / Net I/σ(I): 5
Reflection shellResolution: 3.2→3.25 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.61 / Mean I/σ(I) obs: 1.3 / % possible all: 97.6

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Unpublished structure

Resolution: 3.2→88.2 Å / Cor.coef. Fo:Fc: 0.8732 / Cor.coef. Fo:Fc free: 0.8258 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.501
RfactorNum. reflection% reflectionSelection details
Rfree0.2553 5764 5.01 %RANDOM
Rwork0.2121 ---
obs0.2143 114945 97.18 %-
Displacement parametersBiso mean: 72.8 Å2
Baniso -1Baniso -2Baniso -3
1-0.4742 Å2-1.8169 Å20.7496 Å2
2---3.6684 Å23.1136 Å2
3---3.1942 Å2
Refine analyzeLuzzati coordinate error obs: 0.644 Å
Refinement stepCycle: 1 / Resolution: 3.2→88.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms45112 0 1563 817 47492
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00947151HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0364156HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d16095SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes1025HARMONIC2
X-RAY DIFFRACTIONt_gen_planes6896HARMONIC5
X-RAY DIFFRACTIONt_it47151HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.27
X-RAY DIFFRACTIONt_other_torsion21.07
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion5742SEMIHARMONIC5
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_contact51815SEMIHARMONIC4
LS refinement shellResolution: 3.2→3.28 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2678 429 5.02 %
Rwork0.2212 8124 -
all0.2236 8553 -
obs--97.18 %
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)
11.6774-0.3587-0.18271.1930.4132.09610.03940.0439-0.0137-0.00910.11950.0024-0.07530.2044-0.159-0.0561-0.1954-0.03170.1506-0.1470.122358.0123-58.4839112.309
22.946-0.1595-0.86681.4680.24133.21920.18710.21820.1971-0.09230.116-0.0801-0.1746-0.2889-0.3031-0.1016-0.1311-0.00870.22610.00380.03829.6821-82.3047174.4053
32.4713-0.86630.51961.827-0.0572.648-0.0296-0.0677-0.18170.27040.16580.2082-0.0319-0.2719-0.13620.1518-0.17320.0230.1678-0.03610.08226.4458-21.3695182.8422
41.94520.22250.16380.94740.82.327-0.03180.0974-0.05270.06150.1841-0.0620.17710.333-0.15240.1723-0.164-0.03910.2-0.18510.190341.2999-118.4554100.7419
51.8532-0.66150.14731.53750.57571.3611-0.1482-0.12210.0280.11780.0446-0.0119-0.1347-0.12350.1036-0.0925-0.22260.0260.2813-0.0930.061912.9822-40.1055133.9094
62.4433-0.24130.15370.70790.28471.8430.1540.4223-0.0639-0.1534-0.14160.0278-0.0895-0.1508-0.01240.0526-0.0951-0.02570.4275-0.21620.093214.695-49.45781.3633
72.539-0.68960.62421.1649-0.18922.70240.05010.2046-0.18250.1599-0.00170.01730.07610.4686-0.04840.1357-0.207-0.06780.6764-0.28890.193354.4207-91.3667201.979
82.72690.0262-0.4281.19320.30384.1046-0.0562-0.21340.0627-0.03760.3413-0.14140.0260.5418-0.28510.3444-0.0735-0.03910.5639-0.38020.25169.8886-39.3642158.0409
93.1999-0.5908-0.22831.49060.74513.9050.0291-0.0748-0.2156-0.02680.13010.00710.45170.404-0.15920.1761-0.24650.00650.4391-0.08150.040353.3526-100.5988149.913
103.6529-0.0670.85651.07270.98313.47980.21170.20860.17950.07290.0036-0.1237-0.28450.4805-0.21520.5368-0.03460.00180.3579-0.06720.034671.879-29.8472209.7608
112.56620.0780.67880.94010.82822.5913-0.05810.17190.15080.0157-0.06070.0492-0.211-0.29870.11880.0842-0.035-0.0920.08-0.05210.02345.7773-58.4702222.5638
123.3954-0.57580.53760.80550.22232.0328-0.0691-0.72890.12340.0304-0.00540.1267-0.2548-0.44310.07450.1747-0.0555-0.03610.666-0.37640.2849-1.2524-103.3244129.1405
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|34 - A|503 }
2X-RAY DIFFRACTION2{ B|34 - B|503 }
3X-RAY DIFFRACTION3{ C|34 - C|503 }
4X-RAY DIFFRACTION4{ D|34 - D|503 }
5X-RAY DIFFRACTION5{ E|34 - E|502 }
6X-RAY DIFFRACTION6{ F|34 - F|503 }
7X-RAY DIFFRACTION7{ G|34 - G|503 }
8X-RAY DIFFRACTION8{ H|34 - H|503 }
9X-RAY DIFFRACTION9{ I|34 - I|503 }
10X-RAY DIFFRACTION10{ J|34 - J|503 }
11X-RAY DIFFRACTION11{ K|34 - K|503 }
12X-RAY DIFFRACTION12{ L|34 - L|502 }

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