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- PDB-6ax1: Structure of human monoacylglycerol lipase bound to a covalent in... -

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Basic information

Entry
Database: PDB / ID: 6ax1
TitleStructure of human monoacylglycerol lipase bound to a covalent inhibitor
ComponentsMonoglyceride lipase
KeywordsHYDROLASE/HYDROLASE Inhibitor / Monoacylglycerol lipase / covalent inhibitor / SBDD / HYDROLASE / 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-C0S / Monoglyceride lipase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.26 Å
AuthorsPandit, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase.
Authors: Butler, C.R. / Beck, E.M. / Harris, A. / Huang, Z. / McAllister, L.A. / Am Ende, C.W. / Fennell, K. / Foley, T.L. / Fonseca, K. / Hawrylik, S.J. / Johnson, D.S. / Knafels, J.D. / Mente, S. / ...Authors: Butler, C.R. / Beck, E.M. / Harris, A. / Huang, Z. / McAllister, L.A. / Am Ende, C.W. / Fennell, K. / Foley, T.L. / Fonseca, K. / Hawrylik, S.J. / Johnson, D.S. / Knafels, J.D. / Mente, S. / Noell, G.S. / Pandit, J. / Phillips, T.B. / Piro, J.R. / Rogers, B.N. / Samad, T.A. / Wang, J. / Wan, S. / Brodney, M.A.
History
DepositionSep 6, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release

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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)77,5847
Polymers76,5172
Non-polymers1,0675
Water7,368409
1
A: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8384
Polymers38,2591
Non-polymers5793
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Monoglyceride lipase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7463
Polymers38,2591
Non-polymers4872
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.360, 126.900, 137.510
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-C0S / 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate


Mass: 395.257 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H11F6N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 409 / 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: 50.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: Reservoir Buffer: 0.07M sodium cacodylate pH 5.1-5.9 and 33-51% MPD The protein is 20 mg/mL in a buffer of 15 mM HEPES pH 8.2; 2 mM TCEP; and 10% glycerol, with hexaethylene glycol ...Details: Reservoir Buffer: 0.07M sodium cacodylate pH 5.1-5.9 and 33-51% MPD The protein is 20 mg/mL in a buffer of 15 mM HEPES pH 8.2; 2 mM TCEP; and 10% glycerol, with hexaethylene glycol monododecyl ether added to 0.1 mM. Apo protein crystals obtained in this manner were transferred to a cryo-protectant solution consisting of 70 mM NaCacodylate pH 5.1; 10% MPD; 30% PEG-MME-2K, and 1mM of inhibitor compound. Crystals were soaked overnight, then flash-frozen in LN2.
PH range: 5.1 - 5.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.26→93.258 Å / Num. all: 34396 / Num. obs: 34396 / % possible obs: 96.4 % / Redundancy: 5.9 % / Biso Wilson estimate: 42.42 Å2 / Rpim(I) all: 0.047 / Rrim(I) all: 0.118 / Rsym value: 0.099 / Net I/av σ(I): 5.2 / Net I/σ(I): 10.9 / Num. measured all: 202567
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.26-2.382.30.4281.8940340410.3080.5290.4282.179
2.38-2.534.60.3542.12174847120.1970.440.3543.496.6
2.53-2.76.70.2872.63082445950.1310.340.2875.3100
2.7-2.926.90.193.92943142380.0840.2220.197.9100
2.92-3.26.70.1325.32661039850.060.1570.13210.8100
3.2-3.586.70.0956.82377735700.0430.1120.09515.2100
3.58-4.136.90.0797.52200231940.0350.0930.07919.6100
4.13-5.066.40.0737.61735226990.0340.0860.07321.6100
5.06-7.156.60.0767.41407321260.0340.0890.07621.4100
7.15-93.2585.90.0717.5734712360.0350.0860.07123.799.9

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
BUSTER-TNTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.26→93.26 Å / Cor.coef. Fo:Fc: 0.9531 / Cor.coef. Fo:Fc free: 0.9387 / SU R Cruickshank DPI: 0.211 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.226 / SU Rfree Blow DPI: 0.173 / SU Rfree Cruickshank DPI: 0.17
RfactorNum. reflection% reflectionSelection details
Rfree0.1984 1735 5.04 %RANDOM
Rwork0.163 ---
obs0.1647 34396 96.2 %-
Displacement parametersBiso max: 158.84 Å2 / Biso mean: 44.77 Å2 / Biso min: 21.8 Å2
Baniso -1Baniso -2Baniso -3
1--1.0284 Å20 Å20 Å2
2--4.5757 Å20 Å2
3----3.5474 Å2
Refinement stepCycle: final / Resolution: 2.26→93.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4362 0 72 409 4843
Biso mean--75.95 53.51 -
Num. residues----563
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1542SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes90HARMONIC2
X-RAY DIFFRACTIONt_gen_planes694HARMONIC5
X-RAY DIFFRACTIONt_it4536HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion563SEMIHARMONIC5
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_contact5293SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4536HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6167HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion3.04
X-RAY DIFFRACTIONt_other_torsion18.02
LS refinement shellResolution: 2.26→2.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2254 104 4.85 %
Rwork0.2022 2039 -
all0.2034 2143 -
obs--96.2 %
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)
10.69030.2004-0.21111.71610.31541.0227-0.0116-0.13-0.01850.0473-0.02050.1454-0.0318-0.04130.032-0.0870.0313-0.0222-0.0932-0.0043-0.0377-24.9528-12.4809-18.451
21.19020.166-0.13862.67270.14740.8386-0.0086-0.0969-0.02480.1409-0.03850.01780.0076-0.00540.0471-0.0551-0.01810.0157-0.12240.0266-0.1094-26.1818-53.1953-19.0744
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A18 - 297
2X-RAY DIFFRACTION2{ B|* }B6 - 296

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