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- PDB-6ovg: L-Methionine Depletion with an Engineered Human Enzyme Disrupts P... -

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Basic information

Entry
Database: PDB / ID: 6ovg
TitleL-Methionine Depletion with an Engineered Human Enzyme Disrupts Prostate Cancer Metabolism
ComponentsCystathionine gamma-lyase
KeywordsLYASE / Engineering
Function / homology
Function and homology information


protein sulfhydration / selenocystathionine gamma-lyase activity / positive regulation of aortic smooth muscle cell differentiation / protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine / homocysteine desulfhydrase / homocysteine desulfhydrase activity / Cysteine formation from homocysteine / Degradation of cysteine and homocysteine / cystathionine gamma-lyase / L-cystine L-cysteine-lyase (deaminating) ...protein sulfhydration / selenocystathionine gamma-lyase activity / positive regulation of aortic smooth muscle cell differentiation / protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine / homocysteine desulfhydrase / homocysteine desulfhydrase activity / Cysteine formation from homocysteine / Degradation of cysteine and homocysteine / cystathionine gamma-lyase / L-cystine L-cysteine-lyase (deaminating) / cystathionine gamma-lyase activity / cysteine biosynthetic process via cystathionine / Metabolism of ingested SeMet, Sec, MeSec into H2Se / hydrogen sulfide biosynthetic process / L-cysteine desulfhydrase activity / cysteine biosynthetic process / cysteine metabolic process / transsulfuration / negative regulation of apoptotic signaling pathway / endoplasmic reticulum unfolded protein response / cellular response to leukemia inhibitory factor / lipid metabolic process / pyridoxal phosphate binding / protein homotetramerization / positive regulation of canonical NF-kappaB signal transduction / calmodulin binding / extracellular exosome / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Cys/Met metabolism enzymes pyridoxal-phosphate attachment site. / Cys/Met metabolism, pyridoxal phosphate-dependent enzyme / Cys/Met metabolism PLP-dependent enzyme / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Cystathionine gamma-lyase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.719 Å
AuthorsYan, W. / Irani, S. / Zhang, J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)R01 GM104896, GM125882, United States
Welch FoundationF-1778 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity.
Authors: Lu, W.C. / Saha, A. / Yan, W. / Garrison, K. / Lamb, C. / Pandey, R. / Irani, S. / Lodi, A. / Lu, X. / Tiziani, S. / Zhang, Y.J. / Georgiou, G. / DiGiovanni, J. / Stone, E.
History
DepositionMay 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 24, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cystathionine gamma-lyase
B: Cystathionine gamma-lyase
C: Cystathionine gamma-lyase
D: Cystathionine gamma-lyase
E: Cystathionine gamma-lyase
F: Cystathionine gamma-lyase
G: Cystathionine gamma-lyase
H: Cystathionine gamma-lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)365,92010
Polymers365,7288
Non-polymers1922
Water6,954386
1
A: Cystathionine gamma-lyase
B: Cystathionine gamma-lyase
C: Cystathionine gamma-lyase
D: Cystathionine gamma-lyase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)183,0566
Polymers182,8644
Non-polymers1922
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18300 Å2
ΔGint-155 kcal/mol
Surface area45390 Å2
MethodPISA
2
E: Cystathionine gamma-lyase
F: Cystathionine gamma-lyase
G: Cystathionine gamma-lyase
H: Cystathionine gamma-lyase


Theoretical massNumber of molelcules
Total (without water)182,8644
Polymers182,8644
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18160 Å2
ΔGint-110 kcal/mol
Surface area45670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)113.558, 164.330, 181.696
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein
Cystathionine gamma-lyase / / Cysteine-protein sulfhydrase / Gamma-cystathionase


Mass: 45716.039 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTH / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P32929, cystathionine gamma-lyase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 2.32 Å3/Da / Density % sol: 46.93 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 30% isopropanol, 150mM sodium citrate 100mM sodium cocadylate pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03321 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 2, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03321 Å / Relative weight: 1
ReflectionResolution: 2.719→50 Å / Num. obs: 175177 / % possible obs: 99.4 % / Redundancy: 6.3 % / Net I/σ(I): 13.109
Reflection shellResolution: 2.719→2.7498 Å / Num. unique obs: 5110

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NMP

2nmp


Resolution: 2.719→49.337 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.229 8804 5.03 %
Rwork0.1806 --
obs0.183 175175 99.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.719→49.337 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23972 0 10 386 24368
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00424521
X-RAY DIFFRACTIONf_angle_d0.67733284
X-RAY DIFFRACTIONf_dihedral_angle_d6.63714598
X-RAY DIFFRACTIONf_chiral_restr0.0473791
X-RAY DIFFRACTIONf_plane_restr0.0054251
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.719-2.74980.28512290.24785110X-RAY DIFFRACTION90
2.7498-2.78220.2982880.23795574X-RAY DIFFRACTION98
2.7822-2.81610.29673130.2325407X-RAY DIFFRACTION99
2.8161-2.85180.33592850.22165554X-RAY DIFFRACTION98
2.8518-2.88930.27933280.21375419X-RAY DIFFRACTION98
2.8893-2.92890.25272790.2135551X-RAY DIFFRACTION99
2.9289-2.97070.28382900.21745497X-RAY DIFFRACTION99
2.9707-3.0150.29212860.21595552X-RAY DIFFRACTION99
3.015-3.06210.30642680.22015598X-RAY DIFFRACTION99
3.0621-3.11230.29523190.20945535X-RAY DIFFRACTION100
3.1123-3.1660.25982540.2035574X-RAY DIFFRACTION99
3.166-3.22360.27892600.22365623X-RAY DIFFRACTION100
3.2236-3.28550.26292520.22485584X-RAY DIFFRACTION100
3.2855-3.35260.27242980.20835602X-RAY DIFFRACTION100
3.3526-3.42550.23283490.19145493X-RAY DIFFRACTION100
3.4255-3.50510.22122900.18245611X-RAY DIFFRACTION100
3.5051-3.59280.23782900.19135563X-RAY DIFFRACTION100
3.5928-3.68990.26182650.18545620X-RAY DIFFRACTION100
3.6899-3.79840.23122670.16935586X-RAY DIFFRACTION100
3.7984-3.9210.22893140.16245612X-RAY DIFFRACTION100
3.921-4.0610.21652810.15225594X-RAY DIFFRACTION100
4.061-4.22360.18023100.1525585X-RAY DIFFRACTION100
4.2236-4.41570.19372850.14965557X-RAY DIFFRACTION100
4.4157-4.64830.2033020.15425597X-RAY DIFFRACTION100
4.6483-4.93930.18442890.14285599X-RAY DIFFRACTION100
4.9393-5.32020.18553370.14485555X-RAY DIFFRACTION100
5.3202-5.85490.19933390.16565551X-RAY DIFFRACTION100
5.8549-6.70030.20963340.17855560X-RAY DIFFRACTION100
6.7003-8.43480.19912640.16465601X-RAY DIFFRACTION100
8.4348-49.34490.19823390.17325507X-RAY DIFFRACTION99

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