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- PDB-9g14: Human LTC4 synthase in complex with compound 2 -

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Basic information

Entry
Database: PDB / ID: 9g14
TitleHuman LTC4 synthase in complex with compound 2
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
: / GLUTATHIONE / PALMITOLEIC ACID / PALMITIC ACID / Leukotriene C4 synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsSrinivas, H.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Not funded 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 9, 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)23,71724
Polymers17,4691
Non-polymers6,24823
Water66737
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)71,15172
Polymers52,4063
Non-polymers18,74569
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_645z+1,x-1,y1
crystal symmetry operation9_654y+1,z,x-11
Buried area22430 Å2
ΔGint-101 kcal/mol
Surface area21250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)178.557, 178.557, 178.557
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, 3 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
#7: Sugar ChemComp-LMT / DODECYL-BETA-D-MALTOSIDE


Type: D-saccharide / Mass: 510.615 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H46O11 / Comment: detergent*YM

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Non-polymers , 7 types, 58 molecules

#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GSH / GLUTATHIONE


Mass: 307.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N3O6S
#5: Chemical
ChemComp-PLM / PALMITIC ACID


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


Mass: 254.408 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C16H30O2
#8: Chemical ChemComp-A1IHS / 1-(phenylmethyl)-9-quinoxalin-2-yl-1,9-diazaspiro[5.5]undecan-2-one


Mass: 386.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N4O / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: Aug 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.24→28.23 Å / Num. obs: 22737 / % possible obs: 99.9 % / Redundancy: 20 % / CC1/2: 1 / Rmerge(I) obs: 0.092 / Rrim(I) all: 0.095 / Net I/σ(I): 22.37
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.24-2.31.26816920.8041.3061
2.3-2.361.23315780.8211.2711
2.36-2.430.96916160.8880.9991
2.43-2.50.74515110.9240.7691
2.5-2.590.54915000.9540.5671
2.59-2.680.4414530.9730.4531
2.68-2.780.33314000.9860.3431
2.78-2.890.28213330.9880.2911
2.89-3.020.20212770.9940.2081
3.02-3.170.16812390.9960.1741
3.17-3.340.11511810.9980.1191
3.34-3.540.09210970.9980.0951
3.54-3.790.06910540.9990.0711
3.79-4.090.0579900.9990.0581
4.09-4.480.0478950.9990.0481
4.48-5.010.0438190.9990.0451
5.01-5.780.0467260.9990.0471
5.78-7.080.0456160.9990.0461
7.08-10.020.03549010.0361
10.02-10.050.03527010.0371

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (26-JUL-2023)refinement
XSCALEdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.24→28.23 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.859 / SU R Cruickshank DPI: 0.145 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.141 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.141
RfactorNum. reflection% reflectionSelection details
Rfree0.2453 1137 5 %RANDOM
Rwork0.2158 ---
obs0.2173 22733 100 %-
Displacement parametersBiso mean: 65.23 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.24→28.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1165 0 280 61 1506
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0071508HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.741976HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d562SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes215HARMONIC5
X-RAY DIFFRACTIONt_it1462HARMONIC10
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.34
X-RAY DIFFRACTIONt_other_torsion9.03
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion172SEMIHARMONIC5
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_contact1138SEMIHARMONIC4
LS refinement shellResolution: 2.24→2.25 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3732 -5.05 %
Rwork0.3408 432 -
all0.3424 455 -
obs--99.76 %
Refinement TLS params.Method: refined / Origin x: 193.577 Å / Origin y: 20.4761 Å / Origin z: 31.059 Å
111213212223313233
T-0.2314 Å2-0.1158 Å2-0.0351 Å2--0.1602 Å2-0.0278 Å2---0.1808 Å2
L1.5627 °2-0.1759 °2-0.1399 °2-5.1988 °22.0332 °2--3.1464 °2
S-0.1227 Å °-0.0516 Å °-0.1968 Å °-0.0255 Å °0.0401 Å °0.5492 Å °0.2235 Å °-0.3311 Å °0.0826 Å °
Refinement TLS groupSelection details: { A|* }

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