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- PDB-8qow: LTA4 hydrolase in complex with compound 2(S) -

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Basic information

Entry
Database: PDB / ID: 8qow
TitleLTA4 hydrolase in complex with compound 2(S)
ComponentsLeukotriene A-4 hydrolase
KeywordsHYDROLASE / LTA4H / Inhibitors
Function / homology
Function and homology information


leukotriene-A4 hydrolase / tripeptide aminopeptidase / tripeptide aminopeptidase activity / leukotriene-A4 hydrolase activity / Biosynthesis of protectins / 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) ...leukotriene-A4 hydrolase / tripeptide aminopeptidase / tripeptide aminopeptidase activity / leukotriene-A4 hydrolase activity / Biosynthesis of protectins / 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) / protein metabolic process / epoxide hydrolase activity / leukotriene biosynthetic process / type I pneumocyte differentiation / peptide catabolic process / response to zinc ion / metalloaminopeptidase activity / aminopeptidase activity / lipid metabolic process / response to peptide hormone / tertiary granule lumen / peptidase activity / ficolin-1-rich granule lumen / Neutrophil degranulation / proteolysis / RNA binding / zinc ion binding / extracellular exosome / extracellular region / nucleoplasm / nucleus / cytosol
Similarity search - Function
Leukotriene A4 hydrolase/leucine aminopeptidase / Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal / Aminopeptidase, leukotriene A4 hydrolase-like / Peptidase M1, LTA-4 hydrolase/aminopeptidase, C-terminal domain superfamily / Leukotriene A4 hydrolase, C-terminal / Leukotriene A4 hydrolase, C-terminal / Aminopeptidase N-like , N-terminal domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Peptidase family M1 domain ...Leukotriene A4 hydrolase/leucine aminopeptidase / Peptidase M1, leukotriene A4 hydrolase/aminopeptidase C-terminal / Aminopeptidase, leukotriene A4 hydrolase-like / Peptidase M1, LTA-4 hydrolase/aminopeptidase, C-terminal domain superfamily / Leukotriene A4 hydrolase, C-terminal / Leukotriene A4 hydrolase, C-terminal / Aminopeptidase N-like , N-terminal domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Armadillo-type fold
Similarity search - Domain/homology
ACETATE ION / IMIDAZOLE / Chem-WID / YTTERBIUM (III) ION / Leukotriene A-4 hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsSrinivas, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase.
Authors: Thoma, G. / Markert, C. / Lueoend, R. / Miltz, W. / Spanka, C. / Bollbuck, B. / Wolf, R.M. / Srinivas, H. / Penno, C.A. / Kiffe, M. / Gajewska, M. / Bednarczyk, D. / Wieczorek, G. / Evans, A. ...Authors: Thoma, G. / Markert, C. / Lueoend, R. / Miltz, W. / Spanka, C. / Bollbuck, B. / Wolf, R.M. / Srinivas, H. / Penno, C.A. / Kiffe, M. / Gajewska, M. / Bednarczyk, D. / Wieczorek, G. / Evans, A. / Beerli, C. / Rohn, T.A.
History
DepositionSep 29, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)70,4478
Polymers69,4441
Non-polymers1,0037
Water8,107450
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area840 Å2
ΔGint2 kcal/mol
Surface area23430 Å2
Unit cell
Length a, b, c (Å)76.845, 87.182, 98.858
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 A(4) hydrolase


Mass: 69443.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LTA4H, LTA4 / Production host: Escherichia coli (E. coli) / References: UniProt: P09960, leukotriene-A4 hydrolase

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Non-polymers , 6 types, 457 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-YB / YTTERBIUM (III) ION


Mass: 173.040 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Yb
#5: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H5N2
#6: Chemical ChemComp-WID / (2~{S})-2-azanyl-3-[3-[4-[3-fluoranyl-5-(1~{H}-pyrazol-5-yl)pyridin-2-yl]oxyphenyl]pyrazol-1-yl]propan-1-ol


Mass: 394.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 450 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.4 Å3/Da / Density % sol: 48.82 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 10% PEG 8000, 0.1 IMIDAZOLE PH 6.8, 0.1 SODIUM ACETATE, 0.005 M YBCL3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 2.35→60.67 Å / Num. obs: 28124 / % possible obs: 99.9 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.2 / Net I/σ(I): 8.8
Reflection shellResolution: 2.35→2.36 Å / Redundancy: 6.9 % / Rmerge(I) obs: 1.44 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 580 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (26-JUL-2023)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FRAU

Resolution: 2.35→38.42 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.89 / SU R Cruickshank DPI: 0.402 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.525 / SU Rfree Blow DPI: 0.255 / SU Rfree Cruickshank DPI: 0.247
RfactorNum. reflection% reflectionSelection details
Rfree0.2367 1400 5.05 %RANDOM
Rwork0.1815 ---
obs0.1843 27701 97.9 %-
Displacement parametersBiso mean: 22.87 Å2
Baniso -1Baniso -2Baniso -3
1-5.9772 Å20 Å20 Å2
2---1.6815 Å20 Å2
3----4.2957 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 2.35→38.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4846 0 47 496 5389
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0075023HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.936828HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1715SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes838HARMONIC5
X-RAY DIFFRACTIONt_it5023HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.32
X-RAY DIFFRACTIONt_other_torsion16.72
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion650SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4665SEMIHARMONIC4
LS refinement shellResolution: 2.35→2.37 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2907 -5.59 %
Rwork0.2072 524 -
all0.2111 555 -
obs--85.49 %
Refinement TLS params.Method: refined / Origin x: -34.0995 Å / Origin y: 3.6577 Å / Origin z: 0.1219 Å
111213212223313233
T0.0151 Å20.0072 Å20.0087 Å2--0.0738 Å2-0.0047 Å2---0.1011 Å2
L0.3131 °20.0289 °20.0388 °2-1.0262 °2-0.0331 °2--0.3031 °2
S-0.0185 Å °-0.0208 Å °-0.0203 Å °0.0477 Å °0.0235 Å °-0.0503 Å °0.0134 Å °0.0075 Å °-0.005 Å °
Refinement TLS groupSelection details: { A|* }

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