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- PDB-9g0u: Human LTC4 synthase in complex with AZD9898 -

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Basic information

Entry
Database: PDB / ID: 9g0u
TitleHuman LTC4 synthase in complex with AZD9898
ComponentsLeukotriene C4 synthase
KeywordsLYASE / LTC4S / Inhibitor
Function / homology
Function and homology information


Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR) / Biosynthesis of maresin conjugates in tissue regeneration (MCTR) / leukotriene-C4 synthase / leukotriene-C4 synthase activity / Biosynthesis of Lipoxins (LX) / Synthesis of 5-eicosatetraenoic acids / leukotriene metabolic process / Transferases; Transferring alkyl or aryl groups, other than methyl groups / Synthesis of Leukotrienes (LT) and Eoxins (EX) / glutathione peroxidase activity ...Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR) / Biosynthesis of maresin conjugates in tissue regeneration (MCTR) / leukotriene-C4 synthase / leukotriene-C4 synthase activity / Biosynthesis of Lipoxins (LX) / Synthesis of 5-eicosatetraenoic acids / leukotriene metabolic process / Transferases; Transferring alkyl or aryl groups, other than methyl groups / Synthesis of Leukotrienes (LT) and Eoxins (EX) / glutathione peroxidase activity / leukotriene biosynthetic process / nuclear outer membrane / long-chain fatty acid biosynthetic process / glutathione transferase activity / enzyme activator activity / nuclear envelope / nuclear membrane / intracellular membrane-bounded organelle / lipid binding / endoplasmic reticulum membrane / endoplasmic reticulum / identical protein binding / membrane
Similarity search - Function
5-lipoxygenase-activating protein / FLAP/GST2/LTC4S, conserved site / FLAP/GST2/LTC4S family signature. / : / Membrane-associated, eicosanoid/glutathione metabolism (MAPEG) protein / Membrane associated eicosanoid/glutathione metabolism-like domain superfamily / MAPEG family
Similarity search - Domain/homology
: / PALMITOLEIC ACID / PALMITIC ACID / Leukotriene C4 synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSrinivas, H.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Other private Switzerland
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase.
Authors: Thoma, G. / Miltz, W. / Waelchli, R. / Orain, D. / Spanka, C. / Decoret, O. / Wolf, R.M. / Hurley, B. / Cheung, A.K. / Sandham, D.A. / Honda, A. / Tichkule, R. / Chen, X. / Patel, T. / Labbe- ...Authors: Thoma, G. / Miltz, W. / Waelchli, R. / Orain, D. / Spanka, C. / Decoret, O. / Wolf, R.M. / Hurley, B. / Cheung, A.K. / Sandham, D.A. / Honda, A. / Tichkule, R. / Chen, X. / Patel, T. / Labbe-Giguere, N. / Tan, K.L. / Springer, C. / Manchester, J. / Culshaw, A.J. / Hunt, P. / Srinivas, H. / Penno, C.A. / Ferrand, S. / Numao, S. / Schopfer, U. / Jager, P. / Wack, N. / Hasler, F. / Urban, B. / Sindelar, M. / Loetscher, P. / Kiffe, M. / Ren, X. / Nicklin, P. / White, K. / Subramanian, K. / Liu, H. / Growcott, E.J. / Rohn, T.A.
History
DepositionJul 8, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leukotriene C4 synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,13322
Polymers17,4691
Non-polymers5,66421
Water46826
1
A: Leukotriene C4 synthase
hetero molecules

A: Leukotriene C4 synthase
hetero molecules

A: Leukotriene C4 synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,39866
Polymers52,4063
Non-polymers16,99263
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555-z,-x,y1
crystal symmetry operation10_555-y,z,-x1
Buried area17790 Å2
ΔGint-78 kcal/mol
Surface area24620 Å2
Unit cell
Length a, b, c (Å)177.590, 177.590, 177.590
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number196
Space group name H-MF23

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Leukotriene C4 synthase / LTC4 synthase / Glutathione S-transferase LTC4 / Leukotriene-C(4) synthase / Leukotriene-C4 synthase


Mass: 17468.596 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LTC4S / Production host: Pichia (fungus)
References: UniProt: Q16873, leukotriene-C4 synthase, Transferases; Transferring alkyl or aryl groups, other than methyl groups
#5: Sugar ChemComp-LMT / DODECYL-BETA-D-MALTOSIDE


Type: D-saccharide / Mass: 510.615 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H46O11 / Comment: detergent*YM

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Non-polymers , 5 types, 46 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C16H32O2
#4: Chemical
ChemComp-PAM / PALMITOLEIC ACID


Mass: 254.408 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C16H30O2
#6: Chemical ChemComp-A1IHJ / (1~{S},2~{S})-2-[5-[[5-chloranyl-2,4-bis(fluoranyl)phenyl]-(2-fluoranyl-2-methyl-propyl)amino]-3-methoxy-pyrazin-2-yl]carbonylcyclopropane-1-carboxylic acid


Mass: 457.831 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19ClF3N3O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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

Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: 10 % PEG8000, LITHIUM SULPHATE 0.5M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 18, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→25 Å / Num. obs: 16143 / % possible obs: 99.9 % / Redundancy: 20 % / CC1/2: 0.999 / Rmerge(I) obs: 0.193 / Rrim(I) all: 0.198 / Net I/σ(I): 14.41
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.5-2.571.811780.69411
2.57-2.641.62211360.74811
2.64-2.711.37611400.80111
2.71-2.81.09911110.8651.1291
2.8-2.890.95510260.8790.981
2.89-2.990.73310540.9350.7511
2.99-3.10.6049650.9550.6191
3.1-3.230.5089710.9640.521
3.23-3.370.3418870.9820.351
3.37-3.540.2858860.9890.2921
3.54-3.730.1918350.9950.1961
3.73-3.950.1448090.9970.1471
3.95-4.230.117220.9980.1121
4.23-4.570.0876990.9980.0891
4.57-50.0856340.9980.0881
5-5.590.0985970.9980.1011
5.59-6.460.1095030.9980.1111
6.46-7.910.0764490.9990.0781
7.91-11.180.0513480.9990.0521
10-100.051930.9990.0521

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→25 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.191 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.187 / SU Rfree Blow DPI: 0.163 / SU Rfree Cruickshank DPI: 0.166
RfactorNum. reflection% reflectionSelection details
Rfree0.22 807 5 %RANDOM
Rwork0.201 ---
obs0.202 16132 100 %-
Displacement parametersBiso mean: 71.54 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: 1 / Resolution: 2.5→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1166 0 250 67 1483
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011455HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.061913HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d543SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes12HARMONIC2
X-RAY DIFFRACTIONt_gen_planes200HARMONIC5
X-RAY DIFFRACTIONt_it1432HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion20.05
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion163SEMIHARMONIC5
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_contact1633SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.67 Å / Rfactor Rfree error: 0 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.348 146 5.02 %
Rwork0.294 2765 -
all0.296 2911 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 24.3297 Å / Origin y: -28.7629 Å / Origin z: -13.474 Å
111213212223313233
T-0.119 Å20.1095 Å20.0439 Å2--0.1458 Å2-0.0397 Å2---0.1361 Å2
L3.2938 °2-0.3989 °2-1.3154 °2-0.99 °20.009 °2--2.6166 °2
S0.0111 Å °-0.0867 Å °-0.3616 Å °0.0645 Å °-0.0884 Å °-0.187 Å °0.2696 Å °0.3845 Å °0.0773 Å °
Refinement TLS groupSelection details: { A|* }

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