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- PDB-3mdr: Tranylcypromine complex of Cytochrome P450 46A1 -

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Basic information

Entry
Database: PDB / ID: 3mdr
TitleTranylcypromine complex of Cytochrome P450 46A1
ComponentsCholesterol 24-hydroxylase
KeywordsOXIDOREDUCTASE / CYP46A1 / P450 46A1 / P450 / TRANYLCYPROMINE / MONOOXYGENASE / METABOLIC ENZYME / HEME / Cholesterol metabolism / Endoplasmic reticulum / Iron / Lipid metabolism / Membrane / Metal-binding / Microsome / NADP / Steroid metabolism / Transmembrane
Function / homology
Function and homology information


cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / bile acid biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / cholesterol catabolic process / steroid hydroxylase activity ...cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / bile acid biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / cholesterol catabolic process / steroid hydroxylase activity / regulation of long-term synaptic potentiation / Endogenous sterols / xenobiotic metabolic process / presynapse / nervous system development / postsynapse / iron ion binding / dendrite / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
Cholesterol 24-hydroxylase / 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
(1R,2S)-2-phenylcyclopropanamine / PROTOPORPHYRIN IX CONTAINING FE / Cholesterol 24-hydroxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsMast, N. / Charvet, C. / Pikuleva, I. / Stout, C.D.
Citation
Journal: J.Biol.Chem. / Year: 2010
Title: Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain.
Authors: Mast, N. / Charvet, C. / Pikuleva, I.A. / Stout, C.D.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2008
Title: Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.
Authors: Mast, N. / White, M.A. / Bjorkhem, I. / Johnson, E.F. / Stout, C.D. / Pikuleva, I.A.
History
DepositionMar 30, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 28, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Sep 6, 2023Group: 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 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cholesterol 24-hydroxylase
B: Cholesterol 24-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,7506
Polymers104,2502
Non-polymers1,4994
Water6,125340
1
A: Cholesterol 24-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,8753
Polymers52,1251
Non-polymers7502
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cholesterol 24-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,8753
Polymers52,1251
Non-polymers7502
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)121.190, 121.190, 143.990
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number80
Space group name H-MI41
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21A

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112B58 - 489
2112A58 - 489
1212B500 - 502
2212A500 - 502

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Components

#1: Protein Cholesterol 24-hydroxylase / / CH24H / Cytochrome P450 46A1


Mass: 52125.086 Da / Num. of mol.: 2 / Fragment: UNP residues 51-500
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP46, CYP46A1 / Plasmid: PUC18 / Production host: Escherichia coli (E. coli) / Strain (production host): DH5ALPHA / References: UniProt: Q9Y6A2, EC: 1.14.13.98
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-GJZ / (1R,2S)-2-phenylcyclopropanamine / Tranylcypromine


Mass: 133.190 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H11N / Comment: inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 340 / Source method: isolated from a natural source / Formula: H2O

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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: 2.57 Å3/Da / Density % sol: 52.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 12% PEG 8000, 20% glycerol, 50 mM KPi, 0.1 M trimethylamine N-oxide, pH 5.8, VAPOR DIFFUSION, SITTING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 10, 2009 / Details: Rh coated flat mirror
RadiationMonochromator: side scattering I-beam bent single crystal, asymmetric cut 4.9650 deg
Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.532
11-H, K, -L20.468
ReflectionResolution: 2→92.72 Å / Num. all: 68703 / Num. obs: 68703 / % possible obs: 98.3 % / Observed criterion σ(F): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 37.5 Å2 / Rmerge(I) obs: 0.068 / Rsym value: 0.068 / Net I/σ(I): 6.7
Reflection shellResolution: 2→2.11 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.532 / Mean I/σ(I) obs: 1.3 / Num. measured all: 32223 / Num. unique all: 9957 / Rsym value: 0.532 / % possible all: 97.9

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Processing

Software
NameVersionClassificationNB
REFMAC5.5.0072refinement
CNSrefinement
PDB_EXTRACT3.1data extraction
Blu-Icedata collection
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
SCALA3.2.25data processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2Q9F

2q9f


Resolution: 2→30 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.921 / Occupancy max: 1 / Occupancy min: 1 / SU B: 4.558 / SU ML: 0.12 / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.047 / ESU R Free: 0.037 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES:REFINED INDIVIDUALLY TWO TWIN DOMAINS: H,K,L TWIN FRACTION 0.532 -H,K,-L TWIN FRACTION 0.468
RfactorNum. reflection% reflectionSelection details
Rfree0.244 3356 5.2 %RANDOM
Rwork0.225 ---
all0.226 68703 --
obs0.226 61785 93.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 82.15 Å2 / Biso mean: 37.984 Å2 / Biso min: 14.04 Å2
Baniso -1Baniso -2Baniso -3
1--3.88 Å20 Å20 Å2
2---3.88 Å20 Å2
3---7.77 Å2
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6876 0 106 340 7322
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.013
X-RAY DIFFRACTIONr_angle_refined_deg1.264
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: B / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
1699TIGHT POSITIONAL0.050.05
1782MEDIUM POSITIONAL0.080.5
1699TIGHT THERMAL0.240.5
1782MEDIUM THERMAL0.362
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 113 -
Rwork0.266 2010 -
all-2123 -
obs-2010 41.46 %

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