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- PDB-6bq0: Structure of human monoacylglycerol lipase bound to a covalent in... -

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Basic information

Entry
Database: PDB / ID: 6bq0
TitleStructure of human monoacylglycerol lipase bound to a covalent inhibitor
ComponentsMonoglyceride lipase
KeywordsHydrolase/Hydrolase Inhibitor / Monoacylglycerol lipase / covalent inhibitor / SBDD / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


Arachidonate production from DAG / acylglycerol catabolic process / Acyl chain remodeling of DAG and TAG / acylglycerol lipase / monoacylglycerol catabolic process / triglyceride catabolic process / regulation of endocannabinoid signaling pathway / monoacylglycerol lipase activity / arachidonic acid metabolic process / regulation of sensory perception of pain ...Arachidonate production from DAG / acylglycerol catabolic process / Acyl chain remodeling of DAG and TAG / acylglycerol lipase / monoacylglycerol catabolic process / triglyceride catabolic process / regulation of endocannabinoid signaling pathway / monoacylglycerol lipase activity / arachidonic acid metabolic process / regulation of sensory perception of pain / lysophospholipase activity / Triglyceride catabolism / regulation of signal transduction / lipid metabolic process / fatty acid biosynthetic process / regulation of inflammatory response / inflammatory response / endoplasmic reticulum membrane / protein homodimerization activity / membrane / plasma membrane / cytosol
Similarity search - Function
Serine aminopeptidase, S33 / Serine aminopeptidase, S33 / Lipases, serine active site. / Alpha/beta hydrolase fold-1 / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-E3A / Monoglyceride lipase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsPandit, J.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation.
Authors: McAllister, L.A. / Butler, C.R. / Mente, S. / O'Neil, S.V. / Fonseca, K.R. / Piro, J.R. / Cianfrogna, J.A. / Foley, T.L. / Gilbert, A.M. / Harris, A.R. / Helal, C.J. / Johnson, D.S. / ...Authors: McAllister, L.A. / Butler, C.R. / Mente, S. / O'Neil, S.V. / Fonseca, K.R. / Piro, J.R. / Cianfrogna, J.A. / Foley, T.L. / Gilbert, A.M. / Harris, A.R. / Helal, C.J. / Johnson, D.S. / Montgomery, J.I. / Nason, D.M. / Noell, S. / Pandit, J. / Rogers, B.N. / Samad, T.A. / Shaffer, C.L. / da Silva, R.G. / Uccello, D.P. / Webb, D. / Brodney, M.A.
History
DepositionNov 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 14, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 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: Monoglyceride lipase
B: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,2864
Polymers76,5172
Non-polymers7692
Water7,981443
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-0 kcal/mol
Surface area22860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.310, 126.620, 138.060
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Monoglyceride lipase / MGL / HU-K5 / Lysophospholipase homolog / Lysophospholipase-like / Monoacylglycerol lipase / MAGL


Mass: 38258.688 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MGLL / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta / References: UniProt: Q99685, acylglycerol lipase
#2: Chemical ChemComp-E3A / 1-({(1R,5S,6r)-6-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carbonyl}oxy)pyrrolidine-2,5-dione


Mass: 384.361 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17FN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 443 / 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: 2.46 Å3/Da / Density % sol: 50.1 % / Mosaicity: 0.314 °
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 0.07M sodium cacodylate pH 5.1-5.9 and 33-51% MPD

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jan 19, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 51178 / % possible obs: 99.8 % / Redundancy: 6.2 % / Biso Wilson estimate: 36.36 Å2 / Rmerge(I) obs: 0.086 / Χ2: 1.047 / Net I/σ(I): 10.4 / Num. measured all: 315405
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2-2.076.30.83950371.033199.6
2.07-2.156.30.61650851.059199.7
2.15-2.256.30.41250661.052199.8
2.25-2.376.30.30150331.073199.8
2.37-2.526.30.23550891.08199.9
2.52-2.716.30.16751171.009199.9
2.71-2.996.30.11350821.031100
2.99-3.426.10.08551471.0091100
3.42-4.315.90.05851971.054199.9
4.31-505.70.04853251.068199.6

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Processing

Software
NameVersionClassification
HKL-2000data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6AX1

6ax1


Resolution: 2→47.88 Å / Cor.coef. Fo:Fc: 0.9602 / Cor.coef. Fo:Fc free: 0.9478 / SU R Cruickshank DPI: 0.14 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.146 / SU Rfree Blow DPI: 0.134 / SU Rfree Cruickshank DPI: 0.132
RfactorNum. reflection% reflectionSelection details
Rfree0.2136 2610 5.1 %RANDOM
Rwork0.1787 ---
obs0.1804 51177 99.62 %-
Displacement parametersBiso max: 151.03 Å2 / Biso mean: 41.69 Å2 / Biso min: 21.49 Å2
Baniso -1Baniso -2Baniso -3
1--0.2363 Å20 Å20 Å2
2--3.5015 Å20 Å2
3----3.2653 Å2
Refine analyzeLuzzati coordinate error obs: 0.211 Å
Refinement stepCycle: final / Resolution: 2→47.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4362 0 60 443 4865
Biso mean--55.09 55.92 -
Num. residues----563
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1551SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes90HARMONIC2
X-RAY DIFFRACTIONt_gen_planes705HARMONIC5
X-RAY DIFFRACTIONt_it4533HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion569SEMIHARMONIC5
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_contact5479SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4533HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6156HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion16.75
LS refinement shellResolution: 2→2.05 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2718 196 5.4 %
Rwork0.2104 3433 -
all0.2138 3629 -
obs--99.62 %

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