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- PDB-7l4u: Crystal structure of human monoacylglycerol lipase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7l4u
TitleCrystal structure of human monoacylglycerol lipase in complex with compound 1h
ComponentsMonoglyceride lipase
KeywordsHYDROLASE/INHIBITOR / Inhibitor / Serine hydrolase / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of retrograde trans-synaptic signaling by endocanabinoid / acylglycerol lipase / varicosity / monoacylglycerol catabolic process / regulation of endocannabinoid signaling pathway / cerebellar climbing fiber to Purkinje cell synapse / monoacylglycerol lipase activity / arachidonate metabolic process / regulation of sensory perception of pain / long-term synaptic depression ...regulation of retrograde trans-synaptic signaling by endocanabinoid / acylglycerol lipase / varicosity / monoacylglycerol catabolic process / regulation of endocannabinoid signaling pathway / cerebellar climbing fiber to Purkinje cell synapse / monoacylglycerol lipase activity / arachidonate metabolic process / regulation of sensory perception of pain / long-term synaptic depression / regulation of axon extension / parallel fiber to Purkinje cell synapse / presynapse / regulation of inflammatory response / membrane / cytosol
Similarity search - Function
: / Serine aminopeptidase, S33 / Serine aminopeptidase, S33 / Alpha/beta hydrolase fold-1 / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-XP7 / Monoglyceride lipase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsQin, L. / Lane, W. / Skene, R.J. / Dougan, D.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Design and Synthesis of Novel Spiro Derivatives as Potent and Reversible Monoacylglycerol Lipase (MAGL) Inhibitors: Bioisosteric Transformation from 3-Oxo-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl Moiety.
Authors: Ikeda, S. / Sugiyama, H. / Tokuhara, H. / Murakami, M. / Nakamura, M. / Oguro, Y. / Aida, J. / Morishita, N. / Sogabe, S. / Dougan, D.R. / Gay, S.C. / Qin, L. / Arimura, N. / Takahashi, Y. / ...Authors: Ikeda, S. / Sugiyama, H. / Tokuhara, H. / Murakami, M. / Nakamura, M. / Oguro, Y. / Aida, J. / Morishita, N. / Sogabe, S. / Dougan, D.R. / Gay, S.C. / Qin, L. / Arimura, N. / Takahashi, Y. / Sasaki, M. / Kamada, Y. / Aoyama, K. / Kimoto, K. / Kamata, M.
History
DepositionDec 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Monoglyceride lipase
B: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,2705
Polymers70,4692
Non-polymers8013
Water2,864159
1
A: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6533
Polymers35,2341
Non-polymers4182
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6172
Polymers35,2341
Non-polymers3831
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.528, 127.453, 135.911
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-559-

HOH

21A-563-

HOH

31A-580-

HOH

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Components

#1: Protein Monoglyceride lipase


Mass: 35234.305 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) / References: UniProt: A0A0C4DFN3
#2: Chemical ChemComp-XP7 / (5S)-5-(3-{4-[(2-chloro-4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxopropyl)pyrrolidin-2-one


Mass: 382.857 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H24ClFN2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.84 Å3/Da / Density % sol: 56.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1M NaOAc pH 5.5, 32-38% MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 34850 / % possible obs: 90.6 % / Redundancy: 6 % / Rmerge(I) obs: 0.112 / Rpim(I) all: 0.049 / Rrim(I) all: 0.123 / Χ2: 1.008 / Net I/σ(I): 8 / Num. measured all: 208839
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.25-2.293.60.5639180.8380.2850.6351.00648.6
2.29-2.333.80.5599710.8370.2750.6260.91951.5
2.33-2.383.90.68811290.7940.3470.7760.97759.3
2.38-2.424.10.73114410.8080.370.8250.98474.6
2.42-2.484.40.94517000.6970.4761.0660.99490
2.48-2.535.30.8818310.7850.4120.9760.99896.2
2.53-2.66.10.90418810.8570.3970.991.00799.8
2.6-2.676.50.7619260.880.3220.8281.05100
2.67-2.756.60.58918900.9270.2470.641.032100
2.75-2.836.60.44119260.9540.1860.4791.035100
2.83-2.946.60.35418880.9710.1490.3851.017100
2.94-3.056.60.30119260.9750.1260.3271.006100
3.05-3.196.60.19919060.9860.0840.2160.98899.8
3.19-3.366.60.15319260.9930.0640.1661.00899.8
3.36-3.576.50.12119190.9940.0510.1321.03299.6
3.57-3.856.50.09419190.9950.040.1030.99899.6
3.85-4.236.40.07719160.9960.0330.0841.02198.9
4.23-4.856.30.05819180.9980.0250.0640.99598.8
4.85-6.16.40.04719420.9990.020.0510.98898
6.1-506.50.02919770.9990.0130.0320.98996

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ZUN

5zun


Resolution: 2.25→34.29 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.938 / SU B: 18.68 / SU ML: 0.207 / SU R Cruickshank DPI: 0.2602 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.26 / ESU R Free: 0.217 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2453 1651 4.7 %RANDOM
Rwork0.1946 ---
obs0.1971 33182 90.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 180.9 Å2 / Biso mean: 53.521 Å2 / Biso min: 22.75 Å2
Baniso -1Baniso -2Baniso -3
1--0.78 Å2-0 Å2-0 Å2
2--0.72 Å2-0 Å2
3---0.07 Å2
Refinement stepCycle: final / Resolution: 2.25→34.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4434 0 53 159 4646
Biso mean--52.91 49.15 -
Num. residues----572
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134604
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174289
X-RAY DIFFRACTIONr_angle_refined_deg1.5471.6486251
X-RAY DIFFRACTIONr_angle_other_deg1.2431.5699940
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.925572
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.25721.689219
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.09215760
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.6191528
X-RAY DIFFRACTIONr_chiral_restr0.0680.2577
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025120
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02936
LS refinement shellResolution: 2.25→2.308 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.402 59 -
Rwork0.353 1297 -
all-1356 -
obs--48.43 %
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)
10.03030.21350.01772.7454-0.49850.7013-0.0647-0.00120.0224-0.1594-0.06940.0235-0.00860.03160.13410.272-0.0179-0.08720.01060.03750.167719.399115.123290.128
20.27340.78050.02892.8387-0.15140.0949-0.0356-0.0656-0.00990.0004-0.0356-0.2-0.0217-0.06450.07120.19840.03990.02580.0542-0.03330.240925.212138.375322.203
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 295
2X-RAY DIFFRACTION1A401
3X-RAY DIFFRACTION2B7 - 294
4X-RAY DIFFRACTION2A402
5X-RAY DIFFRACTION2B401

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