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- PDB-9f8a: Crystal structure of human monoacylglycerol lipase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 9f8a
TitleCrystal structure of human monoacylglycerol lipase in complex with compound 7a
ComponentsMonoglyceride lipase
KeywordsHYDROLASE / ALPHA/BETA HYDROLASE / SERINE ESTERASE
Function / homology
Function and homology information


Arachidonate production from DAG / Acyl chain remodeling of DAG and TAG / acylglycerol lipase / acylglycerol catabolic process / monoacylglycerol catabolic process / regulation of endocannabinoid signaling pathway / triglyceride catabolic process / monoacylglycerol lipase activity / arachidonate metabolic process / regulation of sensory perception of pain ...Arachidonate production from DAG / Acyl chain remodeling of DAG and TAG / acylglycerol lipase / acylglycerol catabolic process / monoacylglycerol catabolic process / regulation of endocannabinoid signaling pathway / triglyceride catabolic process / monoacylglycerol lipase activity / arachidonate metabolic process / regulation of sensory perception of pain / lysophospholipase activity / Triglyceride catabolism / regulation of signal transduction / lipid metabolic process / fatty acid biosynthetic process / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / 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
Similarity search - Domain/homology
: / Monoglyceride lipase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsKuhn, B. / Ritter, M. / Hornsperger, B. / Bell, C. / Kocer, B. / Rombach, D. / Richter, H. / Grether, U. / Gobbi, L. / Kuratli, M. ...Kuhn, B. / Ritter, M. / Hornsperger, B. / Bell, C. / Kocer, B. / Rombach, D. / Richter, H. / Grether, U. / Gobbi, L. / Kuratli, M. / Collin, L. / Benz, J.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Not funded Switzerland
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Discovery of cis -Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors.
Authors: Kuhn, B. / Ritter, M. / Hornsperger, B. / Bell, C. / Kocer, B. / Rombach, D. / Lutz, M.D.R. / Gobbi, L. / Kuratli, M. / Bartelmus, C. / Burkler, M. / Koller, R. / Tosatti, P. / Ruf, I. / ...Authors: Kuhn, B. / Ritter, M. / Hornsperger, B. / Bell, C. / Kocer, B. / Rombach, D. / Lutz, M.D.R. / Gobbi, L. / Kuratli, M. / Bartelmus, C. / Burkler, M. / Koller, R. / Tosatti, P. / Ruf, I. / Guerard, M. / Pavlovic, A. / Stephanus, J. / O'Hara, F. / Wetzl, D. / Saal, W. / Stihle, M. / Roth, D. / Hug, M. / Huber, S. / Heer, D. / Kroll, C. / Topp, A. / Schneider, M. / Gertsch, J. / Glasmacher, S. / van der Stelt, M. / Martella, A. / Wittwer, M.B. / Collin, L. / Benz, J. / Richter, H. / Grether, U.
History
DepositionMay 6, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8393
Polymers35,4661
Non-polymers3732
Water5,296294
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area120 Å2
ΔGint-9 kcal/mol
Surface area12950 Å2
Unit cell
Length a, b, c (Å)89.877, 127.166, 62.672
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 35465.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MGLL / Production host: Escherichia coli (E. coli) / References: UniProt: Q99685, acylglycerol lipase
#2: Chemical ChemComp-A1IA0 / 6-[4-(phenylmethyl)piperidin-1-yl]carbonyl-4~{H}-1,4-benzoxazin-3-one


Mass: 350.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / Source method: isolated from a natural source / Formula: H2O
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

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M MES, pH 6.5 6 %w/v PEG MME 5K 12 %v/v iso-propanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 21, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99976 Å / Relative weight: 1
ReflectionResolution: 1.56→47.66 Å / Num. obs: 51245 / % possible obs: 99.6 % / Redundancy: 7.37 % / CC1/2: 0.999 / Rmerge(I) obs: 0.09 / Net I/σ(I): 9.13
Reflection shellResolution: 1.56→1.66 Å / Rmerge(I) obs: 0.91 / Num. unique obs: 8579 / CC1/2: 0.348

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
SADABSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.56→47.66 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.956 / SU R Cruickshank DPI: 0.072 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.076 / SU Rfree Blow DPI: 0.073 / SU Rfree Cruickshank DPI: 0.07
RfactorNum. reflection% reflectionSelection details
Rfree0.198 2435 4.76 %RANDOM
Rwork0.18 ---
obs0.181 51197 99.6 %-
Displacement parametersBiso mean: 33.7 Å2
Baniso -1Baniso -2Baniso -3
1--8.3294 Å20 Å20 Å2
2--7.1109 Å20 Å2
3---1.2185 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: 1 / Resolution: 1.56→47.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2283 0 27 294 2604
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012437HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.013334HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d856SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes375HARMONIC5
X-RAY DIFFRACTIONt_it2437HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion15.48
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion310SEMIHARMONIC5
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_contact3123SEMIHARMONIC4
LS refinement shellResolution: 1.56→1.6 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2677 187 5.06 %
Rwork0.2746 3509 -
all0.2743 3696 -
obs--98.97 %
Refinement TLS params.Method: refined / Origin x: 117.753 Å / Origin y: 20.9541 Å / Origin z: 0.2994 Å
111213212223313233
T0.0024 Å2-0.0029 Å2-0.0058 Å2--0.0896 Å2-0.0035 Å2---0.0893 Å2
L0.1822 °2-0.3925 °2-0.0429 °2-2.4126 °20.1302 °2--0.9358 °2
S-0.018 Å °-0.0168 Å °0.0231 Å °0.1033 Å °0.0081 Å °-0.0597 Å °-0.06 Å °0.0086 Å °0.01 Å °
Refinement TLS groupSelection details: { A|* }

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