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- PDB-4xry: Human Cytochrome P450 2D6 BACE1 Inhibitor 5 Complex -

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Basic information

Entry
Database: PDB / ID: 4xry
TitleHuman Cytochrome P450 2D6 BACE1 Inhibitor 5 Complex
ComponentsCytochrome P450 2D6
KeywordsOXIDOREDUCTASE / CYP2D6 / P450 2D6 / Cytochrome P450 / MONOOXYGENASE / BACE1
Function / homology
Function and homology information


negative regulation of binding / negative regulation of organofluorine metabolic process / Miscellaneous substrates / isoquinoline alkaloid metabolic process / Fatty acids / coumarin metabolic process / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor / CYP2E1 reactions / arachidonate metabolic process / anandamide 8,9 epoxidase activity ...negative regulation of binding / negative regulation of organofluorine metabolic process / Miscellaneous substrates / isoquinoline alkaloid metabolic process / Fatty acids / coumarin metabolic process / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor / CYP2E1 reactions / arachidonate metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / alkaloid metabolic process / oxidative demethylation / Xenobiotics / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen / long-chain fatty acid biosynthetic process / retinol metabolic process / estrogen metabolic process / Aspirin ADME / steroid metabolic process / xenobiotic catabolic process / cholesterol metabolic process / xenobiotic metabolic process / monooxygenase activity / oxidoreductase activity / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / mitochondrion / cytoplasm
Similarity search - Function
Cytochrome P450, E-class, group I, CYP2D-like / : / 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 ...Cytochrome P450, E-class, group I, CYP2D-like / : / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-SI5 / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsJohnson, E.F. / Fan, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM031001 United States
CitationJournal: J.Med.Chem. / Year: 2015
Title: Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug-Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors.
Authors: Brodney, M.A. / Beck, E.M. / Butler, C.R. / Barreiro, G. / Johnson, E.F. / Riddell, D. / Parris, K. / Nolan, C.E. / Fan, Y. / Atchison, K. / Gonzales, C. / Robshaw, A.E. / Doran, S.D. / ...Authors: Brodney, M.A. / Beck, E.M. / Butler, C.R. / Barreiro, G. / Johnson, E.F. / Riddell, D. / Parris, K. / Nolan, C.E. / Fan, Y. / Atchison, K. / Gonzales, C. / Robshaw, A.E. / Doran, S.D. / Bundesmann, M.W. / Buzon, L. / Dutra, J. / Henegar, K. / LaChapelle, E. / Hou, X. / Rogers, B.N. / Pandit, J. / Lira, R. / Martinez-Alsina, L. / Mikochik, P. / Murray, J.C. / Ogilvie, K. / Price, L. / Sakya, S.M. / Yu, A. / Zhang, Y. / O'Neill, B.T.
History
DepositionJan 21, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Database references ...Author supporting evidence / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_struct_oper_list / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 1.2Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 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
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_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.ptnr1_symmetry / _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_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 2D6
B: Cytochrome P450 2D6
C: Cytochrome P450 2D6
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,95829
Polymers214,9224
Non-polymers5,03625
Water3,279182
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9737
Polymers53,7311
Non-polymers1,2436
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9086
Polymers53,7311
Non-polymers1,1775
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,0398
Polymers53,7311
Non-polymers1,3087
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,0398
Polymers53,7311
Non-polymers1,3087
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.064, 192.341, 247.304
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Cytochrome P450 2D6 / CYPIID6 / Cytochrome P450-DB1 / Debrisoquine 4-hydroxylase


Mass: 53730.566 Da / Num. of mol.: 4 / Fragment: UNP residues 34-497
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2D6, CYP2DL1 / Plasmid: pCWori / Production host: Escherichia coli (E. coli) / Strain (production host): DH5alpha / References: UniProt: P10635, unspecific monooxygenase
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-SI5 / (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine


Mass: 364.413 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H18F2N4OS
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 3.16 Å3/Da / Density % sol: 61.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. Beta- ...Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. Beta-secretase inhibitor was added to the mother liquor after crystallization of the P450 2D6 thiordidazine ternary complex.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.5→39.16 Å / Num. obs: 95062 / % possible obs: 99.6 % / Redundancy: 6.6 % / Biso Wilson estimate: 46.49 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 27.8
Reflection shellResolution: 2.5→2.54 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.397 / Mean I/σ(I) obs: 5.2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TBG

3tbg


Resolution: 2.5→39.16 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.08 / Phase error: 27.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2513 4761 5.02 %Random selection
Rwork0.2076 ---
obs0.2098 94850 99.39 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.8 Å2
Refinement stepCycle: LAST / Resolution: 2.5→39.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14376 0 289 182 14847
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00315117
X-RAY DIFFRACTIONf_angle_d0.69220567
X-RAY DIFFRACTIONf_dihedral_angle_d12.8775587
X-RAY DIFFRACTIONf_chiral_restr0.0242231
X-RAY DIFFRACTIONf_plane_restr0.0032740
LS refinement shellResolution: 2.5→2.54 Å / Rfactor Rfree: 0.2995 / Rfactor Rwork: 0.2538

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