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- PDB-2r59: Leukotriene A4 hydrolase complexed with inhibitor RB3041 -

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Basic information

Entry
Database: PDB / ID: 2r59
TitleLeukotriene A4 hydrolase complexed with inhibitor RB3041
ComponentsLeukotriene A-4 hydrolase
KeywordsHYDROLASE / transition state / analogue peptide / hydrolysis / Alternative splicing / Cytoplasm / Leukotriene biosynthesis / Metal-binding / Metalloprotease / Multifunctional enzyme / Protease / Zinc
Function / homology
Function and homology information


leukotriene-A4 hydrolase / leukotriene-A4 hydrolase activity / tripeptide aminopeptidase activity / tripeptide aminopeptidase / Biosynthesis of protectins / protein metabolic process / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins ...leukotriene-A4 hydrolase / leukotriene-A4 hydrolase activity / tripeptide aminopeptidase activity / tripeptide aminopeptidase / Biosynthesis of protectins / protein metabolic process / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins / Synthesis of Leukotrienes (LT) and Eoxins (EX) / epoxide hydrolase activity / leukotriene biosynthetic process / response to zinc ion / peptide catabolic process / type I pneumocyte differentiation / metalloaminopeptidase activity / aminopeptidase activity / response to peptide hormone / lipid metabolic process / tertiary granule lumen / peptidase activity / ficolin-1-rich granule lumen / Neutrophil degranulation / proteolysis / RNA binding / extracellular exosome / extracellular region / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal domain / Leukotriene A4 hydrolase/leucine aminopeptidase / Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal / Peptidase M1, LTA-4 hydrolase/aminopeptidase, C-terminal domain superfamily / : / Leukotriene A4 hydrolase, C-terminal / Leukotriene A4 hydrolase, C-terminal / Aminopeptidase, leukotriene A4 hydrolase-like / Zincin-like - #30 / Zincin-like ...Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal domain / Leukotriene A4 hydrolase/leucine aminopeptidase / Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal / Peptidase M1, LTA-4 hydrolase/aminopeptidase, C-terminal domain superfamily / : / Leukotriene A4 hydrolase, C-terminal / Leukotriene A4 hydrolase, C-terminal / Aminopeptidase, leukotriene A4 hydrolase-like / Zincin-like - #30 / Zincin-like / tricorn interacting facor f3 domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-terminal domain / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy / Neutral Protease Domain 2 / Neutral Protease; domain 2 / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ACETIC ACID / Chem-PH0 / YTTERBIUM (III) ION / Leukotriene A-4 hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.89 Å
AuthorsTholander, F. / Haeggstrom, J.Z. / Thunnissen, M. / Muroya, A. / Roques, B.P. / Fournie-Zaluski, M.C.
Citation
Journal: Chem.Biol. / Year: 2008
Title: Structure-based dissection of the active site chemistry of leukotriene a4 hydrolase: implications for m1 aminopeptidases and inhibitor design.
Authors: Tholander, F. / Muroya, A. / Roques, B.P. / Fournie-Zaluski, M.C. / Thunnissen, M.M. / Haeggstrom, J.Z.
#1: Journal: Proteins / Year: 2007
Title: Assay for rapid analysis of the tri-peptidase activity of LTA4 hydrolase.
Authors: Tholander, F. / Haeggstrom, J.Z.
#2: Journal: J.Biol.Chem. / Year: 2004
Title: Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates.
Authors: Rudberg, P.C. / Tholander, F. / Andberg, M. / Thunnissen, M.M. / Haeggstrom, J.Z.
#3: Journal: J.Biol.Chem. / Year: 2002
Title: Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms.
Authors: Rudberg, P.C. / Tholander, F. / Thunnissen, M.M. / Haeggstrom, J.Z.
#4: Journal: Proc.Natl.Acad.Sci.Usa / Year: 2002
Title: Leukotriene A4 hydrolase: selective abrogation of leukotriene B4 formation by mutation of aspartic acid 375.
Authors: Rudberg, P.C. / Tholander, F. / Thunnissen, M.M. / Samuelsson, B. / Haeggstrom, J.Z.
#5: Journal: Nat.Struct.Biol. / Year: 2001
Title: Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation.
Authors: Thunnissen, M.M. / Nordlund, P. / Haeggstrom, J.Z.
History
DepositionSep 3, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 7, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3Nov 20, 2019Group: Database references / Derived calculations
Category: pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif
Item: _struct_ref_seq_dif.details
Revision 1.4Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / 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.ptnr1_symmetry / _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_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.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Leukotriene A-4 hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,8555
Polymers70,0621
Non-polymers7934
Water7,116395
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.210, 87.230, 99.230
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Leukotriene A-4 hydrolase / LTA-4 hydrolase / Leukotriene A4 / hydrolase


Mass: 70061.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LTA4H, LTA4 / Plasmid: pT7T3 / Production host: Escherichia coli (E. coli) / Strain (production host): JM101 / References: UniProt: P09960, leukotriene-A4 hydrolase

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Non-polymers , 5 types, 399 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-YB / YTTERBIUM (III) ION


Mass: 173.040 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Yb
#4: Chemical ChemComp-PH0 / N-{(2S)-3-[(R)-[(1R)-1-amino-2-phenylethyl](hydroxy)phosphoryl]-2-benzylpropanoyl}-L-phenylalanine


Mass: 494.519 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31N2O5P
#5: Chemical ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H4O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 395 / 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: 2.42 Å3/Da / Density % sol: 49.08 %
Crystal growTemperature: 298 K / Method: liquid diffusion
Details: Co-crystallized with LTA4H by liquid-liquid diffusion in melting-point capillaries. A Tris-buffered (10 mM, pH 7.5) solution of protein and inhibitor in approximately equimolar ...Details: Co-crystallized with LTA4H by liquid-liquid diffusion in melting-point capillaries. A Tris-buffered (10 mM, pH 7.5) solution of protein and inhibitor in approximately equimolar concentrations (~70 microM) was layered on the precipitate solution containing 28% (weight/volume) polyethylene glycol (Mw 8000), 50 mM Na acetate, 100 mM imidazole, pH 6.8, and 5 mM YbCl3, LIQUID DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I711 / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 16, 2005
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.89→65.515 Å / Num. all: 53141 / Num. obs: 53141 / % possible obs: 97.5 % / Observed criterion σ(F): 1 / Redundancy: 5.7 % / Rmerge(I) obs: 0.078 / Rsym value: 0.078 / Net I/σ(I): 6.2
Reflection shellResolution: 1.89→2 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.26 / Mean I/σ(I) obs: 2.7 / Num. measured all: 42392 / Num. unique all: 7434 / Rsym value: 0.26 / % possible all: 94.9

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
REFMACrefinement
PDB_EXTRACT3data extraction
MAR345dtbdata collection
XSCALEdata scaling
XFITdata reduction
RefinementStarting model: pdb entry1H19

Resolution: 1.89→14.85 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.926 / SU B: 2.944 / SU ML: 0.089 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.142 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.227 1763 3.3 %RANDOM
Rwork0.175 ---
all0.176 53091 --
obs0.176 53091 97.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.108 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20 Å2
2---2.22 Å20 Å2
3---2.11 Å2
Refinement stepCycle: LAST / Resolution: 1.89→14.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4877 0 37 399 5313
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0225042
X-RAY DIFFRACTIONr_angle_refined_deg1.7171.9696853
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0865609
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.4624.439223
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.24615860
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.821523
X-RAY DIFFRACTIONr_chiral_restr0.1260.2761
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023803
X-RAY DIFFRACTIONr_nbd_refined0.2120.22350
X-RAY DIFFRACTIONr_nbtor_refined0.3140.23479
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2427
X-RAY DIFFRACTIONr_metal_ion_refined0.1410.27
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2690.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1380.216
X-RAY DIFFRACTIONr_mcbond_it1.241.53144
X-RAY DIFFRACTIONr_mcangle_it1.86324966
X-RAY DIFFRACTIONr_scbond_it3.00732185
X-RAY DIFFRACTIONr_scangle_it4.5054.51887
LS refinement shellResolution: 1.89→1.944 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.254 131 -
Rwork0.191 3465 -
all-3596 -
obs-3465 90.28 %

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