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- PDB-5sym: Cocrystal structure of the human acyl protein thioesterase 1 with... -

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Basic information

Entry
Database: PDB / ID: 5sym
TitleCocrystal structure of the human acyl protein thioesterase 1 with an isoform-selective inhibitor, ML348
ComponentsAcyl-protein thioesterase 1
Keywordshydrolase/hydrolase inhibitor / hydrolase / inhibitor / thioesterase / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


protein depalmitoylation / palmitoyl[protein] hydrolase / palmitoyl-(protein) hydrolase activity / negative regulation of Golgi to plasma membrane protein transport / phospholipase activity / lipase activity / lysophospholipase activity / Hydrolases; Acting on ester bonds; Thioester hydrolases / carboxylic ester hydrolase activity / fatty acid transport ...protein depalmitoylation / palmitoyl[protein] hydrolase / palmitoyl-(protein) hydrolase activity / negative regulation of Golgi to plasma membrane protein transport / phospholipase activity / lipase activity / lysophospholipase activity / Hydrolases; Acting on ester bonds; Thioester hydrolases / carboxylic ester hydrolase activity / fatty acid transport / eNOS activation / fatty acid metabolic process / RAS processing / nuclear membrane / cell surface / endoplasmic reticulum / extracellular exosome / nucleoplasm / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Phospholipase/carboxylesterase/thioesterase / Phospholipase/Carboxylesterase / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-71Q / Acyl-protein thioesterase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsStuckey, J.A. / Labby, K.J. / Meagher, J.L. / Won, S.J. / Martin, B.R.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R00 CA151460 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)DP2 GM114848 United States
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2).
Authors: Won, S.J. / Davda, D. / Labby, K.J. / Hwang, S.Y. / Pricer, R. / Majmudar, J.D. / Armacost, K.A. / Rodriguez, L.A. / Rodriguez, C.L. / Chong, F.S. / Torossian, K.A. / Palakurthi, J. / Hur, E. ...Authors: Won, S.J. / Davda, D. / Labby, K.J. / Hwang, S.Y. / Pricer, R. / Majmudar, J.D. / Armacost, K.A. / Rodriguez, L.A. / Rodriguez, C.L. / Chong, F.S. / Torossian, K.A. / Palakurthi, J. / Hur, E.S. / Meagher, J.L. / Brooks, C.L. / Stuckey, J.A. / Martin, B.R.
History
DepositionAug 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2016Group: Database references
Revision 1.2Dec 28, 2016Group: Database references
Revision 1.3Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acyl-protein thioesterase 1
B: Acyl-protein thioesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,79315
Polymers49,3852
Non-polymers1,40813
Water6,539363
1
A: Acyl-protein thioesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,58711
Polymers24,6931
Non-polymers89510
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Acyl-protein thioesterase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2064
Polymers24,6931
Non-polymers5133
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.670, 73.690, 81.820
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Acyl-protein thioesterase 1 / / hAPT1 / Lysophospholipase 1 / Lysophospholipase I / LysoPLA I


Mass: 24692.543 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LYPLA1, APT1, LPL1 / Production host: Escherichia coli (E. coli)
References: UniProt: O75608, Hydrolases; Acting on ester bonds; Thioester hydrolases
#2: Chemical ChemComp-71Q / N-[2-chloro-5-(trifluoromethyl)phenyl]-2-[4-(furan-2-carbonyl)piperazin-1-yl]acetamide


Mass: 415.794 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17ClF3N3O3
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 363 / 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: 2.19 Å3/Da / Density % sol: 43.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 0.1M sodium citrate, 22-24% PEG 3350, 200 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.9792 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 4, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.55→43.51 Å / Num. obs: 63533 / % possible obs: 100 % / Redundancy: 8.1 % / Biso Wilson estimate: 18.1 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.022 / Rrim(I) all: 0.063 / Net I/σ(I): 18.5 / Num. measured all: 516543 / Scaling rejects: 417
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.55-1.577.80.4492450731330.9130.1710.4814.2100
8.48-43.5160.02727104520.9990.0120.033597.6

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Processing

Software
NameVersionClassification
BUSTER-TNT2.10.2refinement
MOLREPphasing
SCALAdata scaling
MOSFLMdata reduction
BUSTERrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: APT1-CHAINA, PDB:1FJ2

1fj2


Resolution: 1.55→43.51 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.941 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.093 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.082 / SU Rfree Blow DPI: 0.078 / SU Rfree Cruickshank DPI: 0.076
RfactorNum. reflection% reflectionSelection details
Rfree0.199 3167 4.98 %RANDOM
Rwork0.179 ---
obs0.18 63533 100 %-
Displacement parametersBiso max: 85.74 Å2 / Biso mean: 19.12 Å2 / Biso min: 4.76 Å2
Baniso -1Baniso -2Baniso -3
1--1.9918 Å20 Å20 Å2
2--1.0325 Å20 Å2
3---0.9593 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.55→43.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3350 0 108 363 3821
Biso mean--24.54 29.6 -
Num. residues----446
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1963SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes80HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1085HARMONIC5
X-RAY DIFFRACTIONt_it7082HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion482SEMIHARMONIC5
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_contact7945SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7082HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg12882HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.75
X-RAY DIFFRACTIONt_other_torsion2.52
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.231 210 4.54 %
Rwork0.2 4411 -
all-4621 -
obs--100 %
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)
10.66270.30591.06040.62370.87323.26170.079-0.0593-0.11330.02870.0457-0.0060.2033-0.1073-0.1247-0.0488-0.0094-0.0057-0.02440.0255-0.031-16.231-25.611-10.731
21.6986-0.6992-0.52910.6272-0.34652.49970.0425-0.0936-0.23580.0150.04290.03220.23370.2395-0.0855-0.06960.018-0.0233-0.02160.0085-0.0167-3.5634-26.5602-12.8091
30.8668-0.05580.07051.022-0.04950.96950.02170.00290.05520.02530.0038-0.0366-0.17670.0175-0.0255-0.0454-0.0169-0.0036-0.04-0.0012-0.0421-11.4076-13.2519-16.7087
40.0989-1.46811.22690.2865-1.36531.33610.00530.07980.0224-0.10450.02330.04020.0431-0.0689-0.0286-0.0265-0.0195-0.0091-0.0012-0.0345-0.0056-18.4517-20.0982-30.5072
50.53821.0910.04381.0898-0.45270.6609-0.0547-0.0497-0.0537-0.00470.09550.08130.09690.0212-0.04080.01240.02090.01730.0344-0.0081-0.0365-25.1258-33.625826.2076
60.20330.009-0.18840.6395-0.51551.8293-0.00350.04850.03780.00840.10830.0774-0.0547-0.1476-0.1049-0.09320.00010.0109-0.00120.0374-0.0394-26.9115-19.105218.1021
70.455-1.06370.64880.82220.98620.22810.00340.01060.0321-0.01390.01450.0468-0.07770.0008-0.0179-0.01170.07690.11290.00610.03230.0682-33.1449-4.283929.0024
81.03630.2214-0.71331.1202-0.84541.35110.0983-0.0390.18180.132-0.00380.0143-0.24760.0812-0.0945-0.0528-0.01620.0191-0.0267-0.0124-0.0385-16.5144-11.190724.05
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|8 - 82}A8 - 82
2X-RAY DIFFRACTION2{A|83 - 106}A83 - 106
3X-RAY DIFFRACTION3{A|107 - 218}A107 - 218
4X-RAY DIFFRACTION4{A|219 - 230}A219 - 230
5X-RAY DIFFRACTION5{B|8 - 19}B8 - 19
6X-RAY DIFFRACTION6{B|20 - 153}B20 - 153
7X-RAY DIFFRACTION7{B|154 - 163}B154 - 163
8X-RAY DIFFRACTION8{B|164 - 230}B164 - 230

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