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- PDB-7l4t: Crystal structure of human monoacylglycerol lipase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7l4t
TitleCrystal structure of human monoacylglycerol lipase in complex with compound 1
ComponentsMonoglyceride lipase
KeywordsHYDROLASE/INHIBITOR / Inhibitor / Serine hydrolase / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


acylglycerol metabolic process / monoacylglycerol lipase activity / membrane
Similarity search - Function
Serine aminopeptidase, S33 / Serine aminopeptidase, S33 / Alpha/beta hydrolase fold-1 / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
ACETATE ION / Chem-XPD / Monoglyceride lipase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsQin, L. / Gay, S.C. / Lane, W. / Skene, R.J.
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 20, 2021Group: Structure summary / Category: audit_author
Revision 1.3Oct 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)71,4789
Polymers70,4692
Non-polymers1,0107
Water5,549308
1
A: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7123
Polymers35,2341
Non-polymers4782
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7666
Polymers35,2341
Non-polymers5325
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.818, 127.378, 136.084
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


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-XPD / 6-{4-[(2-chloro-4-fluorophenoxy)methyl]piperidine-1-carbonyl}-2H-1,4-benzoxazin-3(4H)-one


Mass: 418.846 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20ClFN2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical
ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.82 Å3/Da / Density % sol: 56.43 %
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: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 40679 / % possible obs: 99.8 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.04 / Rrim(I) all: 0.097 / Χ2: 1.003 / Net I/σ(I): 8.1 / Num. measured all: 289576
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allΧ2% possible allRrim(I) all
2.2-2.245.40.96819880.8380.4360.96398
2.24-2.2860.94419970.8170.4111.01599.5
2.28-2.326.70.86719840.9030.360.95699.90.94
2.32-2.377.10.93620300.9040.3750.991100
2.37-2.427.30.84420220.9090.3331.0041000.908
2.42-2.487.40.81120230.9040.3181.0181000.872
2.48-2.547.50.64420120.9350.2511.0211000.691
2.54-2.617.40.53120070.9640.2081.011000.57
2.61-2.697.50.42720020.9730.1671.0461000.458
2.69-2.777.40.33920320.9790.1331.0091000.365
2.77-2.877.40.25320340.9860.0990.9961000.272
2.87-2.997.40.21620200.9890.0851.0061000.232
2.99-3.127.40.16320260.9920.0640.991000.176
3.12-3.297.40.12220330.9960.0480.9841000.132
3.29-3.497.30.10620450.9950.0421.0151000.114
3.49-3.767.20.08220340.9970.0331.021000.089
3.76-4.147.20.06820760.9960.0281.0241000.074
4.14-4.7470.04920550.9980.020.9881000.053
4.74-5.977.20.04120800.9990.0160.9871000.044
5.97-507.10.03221790.9990.0130.99899.60.034

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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: 2.2→42.77 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.949 / SU B: 13.486 / SU ML: 0.162 / SU R Cruickshank DPI: 0.1973 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.197 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2262 2012 4.9 %RANDOM
Rwork0.1762 ---
obs0.1786 38667 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 156.4 Å2 / Biso mean: 54.16 Å2 / Biso min: 20.76 Å2
Baniso -1Baniso -2Baniso -3
1-3.14 Å20 Å20 Å2
2---3.51 Å20 Å2
3---0.37 Å2
Refinement stepCycle: final / Resolution: 2.2→42.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4451 0 69 308 4828
Biso mean--83.94 53.72 -
Num. residues----576
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0124627
X-RAY DIFFRACTIONr_angle_refined_deg1.2271.6386289
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1245576
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.5321.651218
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.79515752
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.6411528
X-RAY DIFFRACTIONr_chiral_restr0.1010.2583
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023522
LS refinement shellResolution: 2.201→2.259 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 139 -
Rwork0.313 2790 -
all-2929 -
obs--97.34 %
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)
10.1001-0.1247-0.20892.29420.15740.9124-00.0510.064-0.0475-0.0236-0.34250.0968-0.16010.02370.1465-0.01480.03420.03250.0120.1173-18.97711.693-49.794
20.11220.2782-0.05181.92270.06570.11140.0246-0.05070.0042-0.0365-0.07140.5283-0.01670.09830.04680.11610.0172-0.02270.1077-0.0160.243-25.261-11.26-18.101
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A7 - 294
2X-RAY DIFFRACTION1A2501 - 2502
3X-RAY DIFFRACTION2B7 - 294
4X-RAY DIFFRACTION2B401 - 405

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