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- PDB-8ede: Crystal structure of covalent inhibitor 2-chloro-N'-(N-(4-chlorop... -

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Basic information

Entry
Database: PDB / ID: 8ede
TitleCrystal structure of covalent inhibitor 2-chloro-N'-(N-(4-chlorophenyl)-N-methylglycyl)acetohydrazide bound to Ubiquitin C-terminal Hydrolase-L1
ComponentsUbiquitin carboxyl-terminal hydrolase isozyme L1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / UCHL1 / deubiquitylating enzyme / inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


axon target recognition / male germ cell proliferation / alpha-2A adrenergic receptor binding / muscle cell development / neuron projection terminus / adult walking behavior / neuromuscular process / eating behavior / axonal transport of mitochondrion / protein deubiquitination ...axon target recognition / male germ cell proliferation / alpha-2A adrenergic receptor binding / muscle cell development / neuron projection terminus / adult walking behavior / neuromuscular process / eating behavior / axonal transport of mitochondrion / protein deubiquitination / regulation of macroautophagy / axon cytoplasm / positive regulation of glycolytic process / negative regulation of MAP kinase activity / ubiquitin binding / response to ischemia / UCH proteinases / cellular response to xenobiotic stimulus / omega peptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / cysteine-type endopeptidase activity / neuronal cell body / ubiquitin protein ligase binding / endoplasmic reticulum membrane / nucleoplasm / cytoplasm / cytosol
Similarity search - Function
Ubiquitin carboxyl-terminal hydrolase family 1 cysteine active-site. / Peptidase C12, ubiquitin carboxyl-terminal hydrolase superfamily / Ubiquitin carboxyl-terminal hydrolase, family 1 / Peptidase C12, ubiquitin carboxyl-terminal hydrolase / Papain-like cysteine peptidase superfamily
Similarity search - Domain/homology
Chem-WEU / Ubiquitin carboxyl-terminal hydrolase isozyme L1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.799 Å
AuthorsPatel, R. / Imhoff, R. / Flaherty, D. / Das, C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Covalent Fragment Screening and Optimization Identifies the Chloroacetohydrazide Scaffold as Inhibitors for Ubiquitin C-terminal Hydrolase L1.
Authors: Imhoff, R.D. / Patel, R. / Safdar, M.H. / Jones, H.B.L. / Pinto-Fernandez, A. / Vendrell, I. / Chen, H. / Muli, C.S. / Krabill, A.D. / Kessler, B.M. / Wendt, M.K. / Das, C. / Flaherty, D.P.
History
DepositionSep 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 10, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ubiquitin carboxyl-terminal hydrolase isozyme L1
B: Ubiquitin carboxyl-terminal hydrolase isozyme L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,6068
Polymers49,7112
Non-polymers8966
Water3,747208
1
A: Ubiquitin carboxyl-terminal hydrolase isozyme L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3034
Polymers24,8551
Non-polymers4483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase isozyme L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3034
Polymers24,8551
Non-polymers4483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)110.003, 110.003, 79.609
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number90
Space group name H-MP4212
Components on special symmetry positions
IDModelComponents
11B-303-

SO4

21A-502-

HOH

31A-513-

HOH

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Components

#1: Protein Ubiquitin carboxyl-terminal hydrolase isozyme L1 / UCH-L1 / Neuron cytoplasmic protein 9.5 / PGP 9.5 / PGP9.5 / Ubiquitin thioesterase L1


Mass: 24855.344 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UCHL1 / Plasmid: pGEX-6P-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 Star DE3 / References: UniProt: P09936, ubiquitinyl hydrolase 1
#2: Chemical ChemComp-WEU / 2-[(4-chlorophenyl)-methyl-amino]-~{N}'-ethanoyl-ethanehydrazide


Mass: 255.701 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H14ClN3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.35 Å3/Da / Density % sol: 48.38 % / Description: Well defined cubic crystal
Crystal growTemperature: 294.15 K / Method: vapor diffusion, sitting drop / Details: 0.1M tri-Sodium citrate 2.4M Ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.799→50 Å / Num. obs: 45890 / % possible obs: 100 % / Redundancy: 12.7 % / Biso Wilson estimate: 30.49 Å2 / Rmerge(I) obs: 0.147 / Rpim(I) all: 0.043 / Rrim(I) all: 0.153 / Χ2: 1.045 / Net I/σ(I): 5.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.8-1.8612.92.22945210.6170.6472.3221.03100
1.86-1.9412.81.71145050.7180.4971.7831.024100
1.94-2.0312.51.13345140.8590.3341.1821.025100
2.03-2.1312.30.69745150.9460.2060.7271.08100
2.13-2.2713.10.47545540.9690.1360.4941.114100
2.27-2.4412.60.3345640.980.0960.3441.072100
2.44-2.6912.60.21945760.9910.0640.2281.067100
2.69-3.08130.15646030.9960.0450.1631.024100
3.08-3.8812.70.10446480.9960.030.1080.995100
3.88-5012.20.07148900.9980.0210.0741.02399.9

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PDB_EXTRACT3.27data extraction
DENZO721.3data reduction
SCALEPACK721.3data scaling
MOLREP1.12_2829phasing
HKL-3000721.3data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ETL

2etl


Resolution: 1.799→45.252 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2267 2371 5.17 %
Rwork0.1928 43467 -
obs0.1946 45838 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 132.55 Å2 / Biso mean: 47.1589 Å2 / Biso min: 16.84 Å2
Refinement stepCycle: final / Resolution: 1.799→45.252 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3386 0 80 213 3679
Biso mean--63.33 48.44 -
Num. residues----438
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083521
X-RAY DIFFRACTIONf_angle_d0.8344742
X-RAY DIFFRACTIONf_chiral_restr0.058516
X-RAY DIFFRACTIONf_plane_restr0.006628
X-RAY DIFFRACTIONf_dihedral_angle_d15.5372133
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.7991-1.83590.38121330.34282533
1.8359-1.87580.35921350.31622500
1.8758-1.91940.34641420.29612512
1.9194-1.96740.32081230.26372544
1.9674-2.02060.28481610.24242488
2.0206-2.08010.26111450.21962522
2.0801-2.14720.24651230.2122524
2.1472-2.22390.2581220.2082568
2.2239-2.3130.22671460.20242491
2.313-2.41820.26841440.21122552
2.4182-2.54570.24481530.20092533
2.5457-2.70520.2731340.20782555
2.7052-2.9140.26441260.2132570
2.914-3.20720.23741290.20352589
3.2072-3.67110.20241400.17192608
3.6711-4.62450.16261550.1422615
4.6245-45.2520.2071600.17872763
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)
13.87960.87222.44824.42261.33336.4361-0.2715-0.3283-0.36611.00550.317-0.03820.7135-0.05770.01260.51850.1370.12960.2970.07120.250637.237410.33224.1373
26.46990.3865-0.94145.7361-0.71683.0464-0.33750.3339-0.78610.12540.29530.89050.608-0.56940.050.2827-0.04860.03630.2642-0.01030.413232.59843.51949.682
32.14821.1260.91122.8737-0.35625.41030.40150.70250.0336-0.8507-0.4129-0.1765-0.0523-0.1247-0.06350.359-0.04250.01420.58180.1140.361246.113720.1378-1.8569
43.799-0.64290.76362.9772-0.28483.3129-0.2916-0.26080.28340.57910.17020.1769-0.4931-0.29930.08460.350.11270.01590.2128-0.02380.235334.886423.59817.1605
53.69520.2335-5.0148-0.0253-0.33496.8486-0.6672-0.5993-0.35880.53520.4017-0.34720.56770.5320.310.57990.17030.02060.41140.03330.308347.610611.690722.9729
63.7103-1.88512.11974.762-0.5793.91880.12930.324-0.3218-0.2685-0.10670.46910.0836-0.0904-0.00490.16380.01960.00650.2212-0.02230.247833.345113.02613.4312
76.6345-6.1698-5.98546.33176.06248.60420.53760.86640.1081-0.1905-0.2608-0.1369-0.3624-0.5901-0.29750.2359-0.00480.05440.170.04980.402139.31123.53258.4846
85.43181.0097-0.80414.2521-3.07576.4318-0.31-0.67670.20790.31990.17260.2282-0.3151-0.31560.15150.33220.1721-0.05140.5404-0.09910.229116.437749.136439.2488
96.79630.4189-0.00414.6692-1.52385.9024-0.5928-0.24231.13640.4240.1749-0.3933-0.87550.77840.38690.36370.0174-0.08730.3131-0.07580.368923.966456.719128.1191
104.2102-6.3183-1.94139.96371.66844.86180.31271.2869-0.5782-0.9457-0.82570.40780.5697-0.27040.38880.8483-0.21310.10640.8584-0.2630.623214.14439.648413.0958
114.8681-0.1434-6.06111.8412-0.58368.8226-0.79580.3327-0.7017-0.00590.27840.04680.8151-0.11060.66940.47520.21530.04580.4030.04010.343924.407337.63724.2547
122.1532-0.6836-0.46992.71-1.14962.9023-0.6627-0.9228-0.44880.43790.173-0.17741.09341.20880.21980.55580.43890.0590.7280.14880.323127.368238.840435.2528
133.25040.36243.69920.01710.39934.2074-0.3887-1.45030.34060.34140.43760.2363-0.0277-0.48430.15570.38280.17950.03830.7081-0.07740.31910.801445.884938.3937
143.8459-1.9846-5.11374.77020.91287.6122-0.13590.1857-0.0401-0.14230.0213-0.33240.43250.51840.10820.26320.0615-0.01540.29020.03860.21525.32645.140920.3051
155.078-1.20524.39037.561-1.48043.8482-0.19831.5050.9241-0.9497-0.0031-0.55010.47880.91850.29540.4848-0.02740.04160.56860.12350.411524.653355.24716.2013
167.3354-2.3416-0.77037.492-2.94654.17640.01470.0980.87440.1148-0.01290.38670.0232-0.0153-0.02860.22730.05090.0170.1218-0.01510.31816.471656.454224.3218
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 26 )A2 - 26
2X-RAY DIFFRACTION2chain 'A' and (resid 27 through 56 )A27 - 56
3X-RAY DIFFRACTION3chain 'A' and (resid 57 through 70 )A57 - 70
4X-RAY DIFFRACTION4chain 'A' and (resid 71 through 136 )A71 - 136
5X-RAY DIFFRACTION5chain 'A' and (resid 137 through 159 )A137 - 159
6X-RAY DIFFRACTION6chain 'A' and (resid 160 through 207 )A160 - 207
7X-RAY DIFFRACTION7chain 'A' and (resid 208 through 221 )A208 - 221
8X-RAY DIFFRACTION8chain 'B' and (resid 1 through 19 )B1 - 19
9X-RAY DIFFRACTION9chain 'B' and (resid 20 through 56 )B20 - 56
10X-RAY DIFFRACTION10chain 'B' and (resid 57 through 70 )B57 - 70
11X-RAY DIFFRACTION11chain 'B' and (resid 71 through 89 )B71 - 89
12X-RAY DIFFRACTION12chain 'B' and (resid 90 through 136 )B90 - 136
13X-RAY DIFFRACTION13chain 'B' and (resid 137 through 159 )B137 - 159
14X-RAY DIFFRACTION14chain 'B' and (resid 160 through 189 )B160 - 189
15X-RAY DIFFRACTION15chain 'B' and (resid 190 through 207 )B190 - 207
16X-RAY DIFFRACTION16chain 'B' and (resid 208 through 221 )B208 - 221

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