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- PDB-8twx: Synthesis and Evaluation of Diaryl Ether Modulators of the Leukot... -

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Entry
Database: PDB / ID: 8twx
TitleSynthesis and Evaluation of Diaryl Ether Modulators of the Leukotriene A4 Hydrolase Aminopeptidase Activity
ComponentsLeukotriene A-4 hydrolase
KeywordsHYDROLASE / Leukotriene A4 hydrolase / 4MDM / Aminipeptidase / Activator
Function / homology
Function and homology information


leukotriene-A4 hydrolase / leukotriene-A4 hydrolase activity / tripeptide aminopeptidase / tripeptide aminopeptidase 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 / protein metabolic process ...leukotriene-A4 hydrolase / leukotriene-A4 hydrolase activity / tripeptide aminopeptidase / tripeptide aminopeptidase 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 / protein metabolic process / Synthesis of Leukotrienes (LT) and Eoxins (EX) / epoxide hydrolase activity / leukotriene biosynthetic process / type I pneumocyte differentiation / response to zinc ion / peptide catabolic process / 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 / extracellular exosome / zinc ion binding / 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 ...: / 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
: / Leukotriene A-4 hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsLee, K.H. / Lee, S.H. / Paige, M. / Noble, S.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1R01HL132287-01 United States
CitationJournal: To be published
Title: Synthesis and Evaluation of Diaryl Ether Modulators of the Leukotriene A4 Hydrolase Aminopeptidase Activity
Authors: Lee, K.H. / Lee, S.H. / Paige, M. / Noble, S.M.
History
DepositionAug 21, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Leukotriene A-4 hydrolase
B: Leukotriene A-4 hydrolase
C: Leukotriene A-4 hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)207,4488
Polymers206,6803
Non-polymers7685
Water8,737485
1
A: Leukotriene A-4 hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,2453
Polymers68,8931
Non-polymers3512
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Leukotriene A-4 hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,2453
Polymers68,8931
Non-polymers3512
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Leukotriene A-4 hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,9592
Polymers68,8931
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)139.579, 139.579, 84.337
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
d_1ens_1
d_2ens_1
d_3ens_1

NCS oper:
IDCodeMatrixVector
1given(0.308826193392, -0.951089968818, 0.00736569681402), (-0.951112022063, -0.308843392826, -0.00129622348238), (0.003507671946, -0.00660529502684, -0.999972032766)69.5663341008, 40.1429948866, -21.9413090106
2given(0.867847678643, -0.49682667943, -0.00191240186197), (0.49682353416, 0.86780914909, 0.00858234589401), (-0.00260433857969, -0.00839829521323, 0.999961342282)69.3788123103, -40.1327901527, -11.4705404225

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Components

#1: Protein Leukotriene A-4 hydrolase


Mass: 68893.391 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LTA4H / Production host: Escherichia coli (E. coli) / References: UniProt: P09960
#2: Chemical ChemComp-VI7 / 5-[4-(4-chlorophenoxy)phenyl]-1H-pyrazol-3-amine


Mass: 285.728 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H12ClN3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 485 / Source method: isolated from a natural source / Formula: H2O
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: 2.29 Å3/Da / Density % sol: 46.38 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop
Details: 60-90 mM magnesium formate dihydrate, 20-25 % PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.41→49.13 Å / Num. obs: 70953 / % possible obs: 100 % / Redundancy: 10.3 % / Biso Wilson estimate: 37.25 Å2 / Rrim(I) all: 0.434 / Net I/σ(I): 2.7
Reflection shellResolution: 2.7→2.81 Å / Rmerge(I) obs: 1.434 / Num. unique obs: 46375

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
DIALSdata reduction
DIALSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→36.09 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 25.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2371 1323 2.85 %
Rwork0.2007 --
obs0.2018 46375 91.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7→36.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14572 0 3 485 15060
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00214948
X-RAY DIFFRACTIONf_angle_d0.49720319
X-RAY DIFFRACTIONf_dihedral_angle_d11.715488
X-RAY DIFFRACTIONf_chiral_restr0.0412259
X-RAY DIFFRACTIONf_plane_restr0.0032586
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.810.35661390.30294466X-RAY DIFFRACTION82
2.81-2.940.3471400.28474531X-RAY DIFFRACTION85
2.94-3.090.30181430.26644827X-RAY DIFFRACTION88
3.09-3.280.27581400.25054998X-RAY DIFFRACTION92
3.28-3.540.25991490.21365113X-RAY DIFFRACTION94
3.54-3.890.24331560.18825202X-RAY DIFFRACTION95
3.89-4.450.20781540.17015252X-RAY DIFFRACTION97
4.46-5.610.18181500.16315342X-RAY DIFFRACTION97
5.61-36.090.18411520.16565321X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.8674-0.04870.06940.88260.35992.2724-0.0053-0.03590.03930.0705-0.0416-0.0086-0.08290.03950.04110.2215-0.01170.01380.21040.03750.219112.063719.07185.6485
21.2718-0.2180.02511.17120.06961.5218-0.03270.1976-0.01880.020.09490.07850.0298-0.1677-0.05730.2859-0.02610.02760.2540.04560.274855.190822.7765-27.6783
30.90360.07750.07210.8103-0.04153.4683-0.0977-0.14410.09230.1333-0.04030.0345-0.5082-0.29660.1040.3744-0.0018-0.04130.2718-0.01020.282970.3808-17.5737-6.0005
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 4 through 701)
2X-RAY DIFFRACTION2(chain 'B' and resid 4 through 701)
3X-RAY DIFFRACTION3(chain 'C' and resid 4 through 701)

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