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- PDB-4ypm: Crystal structure of a LonA protease domain in complex with bortezomib -

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Basic information

Entry
Database: PDB / ID: 4ypm
TitleCrystal structure of a LonA protease domain in complex with bortezomib
ComponentsLon proteaseLon protease family
KeywordsHYDROLASE / AAA+ domain / Lon protease / protease domain / Magnesium / Bortezomib
Function / homology
Function and homology information


endopeptidase La / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / cellular response to heat / sequence-specific DNA binding / serine-type endopeptidase activity / ATP hydrolysis activity / ATP binding / identical protein binding / cytoplasm
Similarity search - Function
Lon protease, bacterial / Lon protease, bacterial/eukaryotic-type / Peptidase S16, active site / ATP-dependent serine proteases, lon family, serine active site. / Lon proteolytic domain profile. / Peptidase S16, Lon proteolytic domain / Lon protease / Lon protease (S16) C-terminal proteolytic domain / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. ...Lon protease, bacterial / Lon protease, bacterial/eukaryotic-type / Peptidase S16, active site / ATP-dependent serine proteases, lon family, serine active site. / Lon proteolytic domain profile. / Peptidase S16, Lon proteolytic domain / Lon protease / Lon protease (S16) C-terminal proteolytic domain / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / PUA-like superfamily / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-BO2 / CITRIC ACID / DI(HYDROXYETHYL)ETHER / Lon protease
Similarity search - Component
Biological speciesMeiothermus taiwanensis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.85 Å
AuthorsLin, C.-C. / Chang, C.-I.
Funding support Taiwan, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology Taiwan
CitationJournal: Structure / Year: 2016
Title: Structural Basis for the Magnesium-Dependent Activation and Hexamerization of the Lon AAA+ Protease.
Authors: Shih-Chieh Su / Chien-Chu Lin / Hui-Chung Tai / Mu-Yueh Chang / Meng-Ru Ho / C Satheesan Babu / Jiahn-Haur Liao / Shih-Hsiung Wu / Yuan-Chih Chang / Carmay Lim / Chung-I Chang /
Abstract: The Lon AAA+ protease (LonA) plays important roles in protein homeostasis and regulation of diverse biological processes. LonA behaves as a homomeric hexamer in the presence of magnesium (Mg(2+)) and ...The Lon AAA+ protease (LonA) plays important roles in protein homeostasis and regulation of diverse biological processes. LonA behaves as a homomeric hexamer in the presence of magnesium (Mg(2+)) and performs ATP-dependent proteolysis. However, it is also found that LonA can carry out Mg(2+)-dependent degradation of unfolded protein substrate in an ATP-independent manner. Here we show that in the presence of Mg(2+) LonA forms a non-secluded hexameric barrel with prominent openings, which explains why Mg(2+)-activated LonA can operate as a diffusion-based chambered protease to degrade unstructured protein and peptide substrates efficiently in the absence of ATP. A 1.85 Å crystal structure of Mg(2+)-activated protease domain reveals Mg(2+)-dependent remodeling of a substrate-binding loop and a potential metal-binding site near the Ser-Lys catalytic dyad, supported by biophysical binding assays and molecular dynamics simulations. Together, these findings reveal the specific roles of Mg(2+) in the molecular assembly and activation of LonA.
History
DepositionMar 13, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 16, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2016Group: Database references
Revision 1.2May 18, 2016Group: Database references / Experimental preparation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lon protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5315
Polymers32,8241
Non-polymers7074
Water4,540252
1
A: Lon protease
hetero molecules
x 6


Theoretical massNumber of molelcules
Total (without water)201,18830
Polymers196,9476
Non-polymers4,24124
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_885-y+3,x-y+3,z1
crystal symmetry operation3_585-x+y,-x+3,z1
crystal symmetry operation4_795-x+2,-y+4,z1
crystal symmetry operation5_465y-1,-x+y+1,z1
crystal symmetry operation6_765x-y+2,x+1,z1
Buried area15270 Å2
ΔGint-84 kcal/mol
Surface area75600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.343, 122.343, 103.125
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number177
Space group name H-MP622

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Lon protease / Lon protease family / ATP-dependent protease La


Mass: 32824.488 Da / Num. of mol.: 1
Fragment: alpha subdomain, protease domain, UNP residues 491-793
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Meiothermus taiwanensis (bacteria) / Gene: lonA1, lon / Production host: Escherichia coli (E. coli) / References: UniProt: A0A059VAZ3, endopeptidase La

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Non-polymers , 5 types, 256 molecules

#2: Chemical ChemComp-BO2 / N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE / BORTEZOMIB / Bortezomib


Mass: 384.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H25BN4O4 / Comment: medication, anticancer*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-CIT / CITRIC ACID / Citric acid


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 252 / 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: 3.39 Å3/Da / Density % sol: 63.76 %
Crystal growTemperature: 295 K / Method: evaporation / pH: 6.5 / Details: 0.2 M sodium citrate pH 6.5 and 10 % PEG 3350

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL15A1 / Wavelength: 0.8 Å
DetectorType: RAYONIX MX325HE / Detector: CCD / Date: Mar 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8 Å / Relative weight: 1
ReflectionResolution: 1.85→20 Å / Num. all: 39226 / Num. obs: 39225 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 21.7 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 33.44
Reflection shellResolution: 1.85→1.92 Å / Mean I/σ(I) obs: 4.629 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
HKL-2000data processing
HKL-2000data scaling
Cootmodel building
RefinementResolution: 1.85→19.85 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.948 / SU B: 2.137 / SU ML: 0.065 / Cross valid method: THROUGHOUT / ESU R: 0.101 / ESU R Free: 0.098 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20094 1924 4.9 %RANDOM
Rwork0.17714 ---
obs0.17835 37301 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.072 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å2-0.05 Å20 Å2
2---0.1 Å20 Å2
3---0.33 Å2
Refinement stepCycle: LAST / Resolution: 1.85→19.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 49 252 2514
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192304
X-RAY DIFFRACTIONr_bond_other_d0.0050.022262
X-RAY DIFFRACTIONr_angle_refined_deg1.3862.0133121
X-RAY DIFFRACTIONr_angle_other_deg0.80535224
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2795289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.24624.15789
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.70315395
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2961516
X-RAY DIFFRACTIONr_chiral_restr0.0780.2352
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212552
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02458
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_it1.2651.9631159
X-RAY DIFFRACTIONr_mcbond_other1.261.9621158
X-RAY DIFFRACTIONr_mcangle_it2.0122.9361447
X-RAY DIFFRACTIONr_mcangle_other2.0132.9381448
X-RAY DIFFRACTIONr_scbond_it2.0212.3121143
X-RAY DIFFRACTIONr_scbond_other2.0142.3081141
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2563.3581673
X-RAY DIFFRACTIONr_long_range_B_refined5.46817.1322716
X-RAY DIFFRACTIONr_long_range_B_other5.10916.5142596
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.851→1.899 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.235 121 -
Rwork0.198 2676 -
obs--99.54 %

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