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- PDB-4y8w: Crystal Structure of Human Cytochrome P450 21A2 Progesterone Complex -

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Basic information

Entry
Database: PDB / ID: 4y8w
TitleCrystal Structure of Human Cytochrome P450 21A2 Progesterone Complex
ComponentsCytochrome P450 21-hydroxylase
KeywordsOXIDOREDUCTASE / steroid hydroxylation / monooxygenases / adrenal steroidogenesis / congenital adrenal hyperplasia / Addison's disease / kinetic isotope effects
Function / homology
Function and homology information


Defective CYP21A2 causes AH3 / steroid 21-monooxygenase / steroid 21-monooxygenase activity / mineralocorticoid biosynthetic process / Mineralocorticoid biosynthesis / glucocorticoid biosynthetic process / Glucocorticoid biosynthesis / sterol metabolic process / steroid biosynthetic process / steroid hydroxylase activity ...Defective CYP21A2 causes AH3 / steroid 21-monooxygenase / steroid 21-monooxygenase activity / mineralocorticoid biosynthetic process / Mineralocorticoid biosynthesis / glucocorticoid biosynthetic process / Glucocorticoid biosynthesis / sterol metabolic process / steroid biosynthetic process / steroid hydroxylase activity / steroid metabolic process / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / Endogenous sterols / steroid binding / monooxygenase activity / iron ion binding / heme binding / endoplasmic reticulum membrane
Similarity search - Function
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 / PROGESTERONE / Steroid 21-hydroxylase / Cytochrome P450 21-hydroxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.64 Å
AuthorsPallan, P.S. / Lei, L. / Egli, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103937 United States
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase: STRUCTURE OF THE ENZYMEPROGESTERONE SUBSTRATE COMPLEX AND RATE-LIMITING C-H BOND CLEAVAGE.
Authors: Pallan, P.S. / Wang, C. / Lei, L. / Yoshimoto, F.K. / Auchus, R.J. / Waterman, M.R. / Guengerich, F.P. / Egli, M.
History
DepositionFeb 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 1.2Jun 3, 2015Group: Database references
Revision 1.3Sep 20, 2017Group: Advisory / Author supporting evidence ...Advisory / Author supporting evidence / Database references / Derived calculations / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_struct_oper_list / pdbx_validate_symm_contact
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
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Sep 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 / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_conn.ptnr2_symmetry / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 21-hydroxylase
B: Cytochrome P450 21-hydroxylase
C: Cytochrome P450 21-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)166,79513
Polymers163,6173
Non-polymers3,17710
Water1,38777
1
A: Cytochrome P450 21-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6625
Polymers54,5391
Non-polymers1,1234
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2350 Å2
ΔGint-46 kcal/mol
Surface area18970 Å2
MethodPISA
2
B: Cytochrome P450 21-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,5664
Polymers54,5391
Non-polymers1,0273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2140 Å2
ΔGint-29 kcal/mol
Surface area19240 Å2
MethodPISA
3
C: Cytochrome P450 21-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,5664
Polymers54,5391
Non-polymers1,0273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2140 Å2
ΔGint-30 kcal/mol
Surface area19490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.383, 86.860, 108.923
Angle α, β, γ (deg.)90.00, 102.11, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Cytochrome P450 21-hydroxylase / Cytochrome P450 / family 21 / subfamily A / polypeptide 2 / isoform CRA_b / DJ34F7.3 (Cytochrome ...Cytochrome P450 / family 21 / subfamily A / polypeptide 2 / isoform CRA_b / DJ34F7.3 (Cytochrome P450 / subfamily XXIA (Steroid 21-hydroxylase / congenital adrenal hyperplasia) / polypeptide 2 (CYP21 / P450c21B)) / Steroid 21-hydroxylase / cDNA / FLJ95495 / Homo sapiens cytochrome P450 / polypeptide 2(CYP21A2) / mRNA


Mass: 54539.160 Da / Num. of mol.: 3 / Fragment: residues 30-495
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Tissue: Adrenal cortex / Gene: P450-CYP21B, CYP21A2, hCG_1999926 / Organ: Kidneys / Plasmid: pET17b / Cell (production host): BL21-Gold DE(3) / Production host: Escherichia coli (E. coli) / References: UniProt: Q16874, UniProt: P08686*PLUS
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C34H32FeN4O4
#4: Chemical ChemComp-STR / PROGESTERONE / Progesterone


Mass: 314.462 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C21H30O2 / Comment: hormone*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.13 Å3/Da / Density % sol: 42.13 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12 mg/mL protein, 0.05 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonate (HEPES), 0.1 M ammonium sulfate and 12.5% (w/v) polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9782 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9782 Å / Relative weight: 1
ReflectionResolution: 2.64→30 Å / Num. obs: 40299 / % possible obs: 100 % / Observed criterion σ(I): 5 / Redundancy: 7.5 % / Net I/σ(I): 10.2
Reflection shellResolution: 2.64→3.42 Å / Redundancy: 7.1 % / Mean I/σ(I) obs: 1.4 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ID: 3QZ1 (One molecule of the protein alone)

3qz1


Resolution: 2.64→30 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.874 / SU B: 18.477 / SU ML: 0.372 / Cross valid method: THROUGHOUT / ESU R Free: 0.411 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.28084 3087 7.7 %RANDOM
Rwork0.23103 ---
obs0.23485 37210 99.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.618 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å2-0 Å2-0.32 Å2
2---0.73 Å2-0 Å2
3---0.62 Å2
Refinement stepCycle: LAST / Resolution: 2.64→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10735 0 20 77 10832
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01911049
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5212.00915099
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.93651311
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.7123.062467
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.016151840
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4591587
X-RAY DIFFRACTIONr_chiral_restr0.0980.21698
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0218295
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.014.2475277
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.8186.3646576
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.9084.2845771
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.03535.04616521
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.64→2.707 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.346 206 -
Rwork0.347 2549 -
obs--93.9 %

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