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- PDB-9h9o: Crystal structure of NEDD4 HECT domain in complex with norclomipramine -

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Basic information

Entry
Database: PDB / ID: 9h9o
TitleCrystal structure of NEDD4 HECT domain in complex with norclomipramine
ComponentsIsoform 4 of E3 ubiquitin-protein ligase NEDD4
KeywordsLIGASE / Ihibitor / Complex / Ubiquitin / E3
Function / homology
Function and homology information


formation of structure involved in a symbiotic process / positive regulation of nucleocytoplasmic transport / negative regulation of sodium ion transport / regulation of potassium ion transmembrane transporter activity / viral budding / nuclear receptor-mediated glucocorticoid signaling pathway / : / phosphothreonine residue binding / receptor catabolic process / apicolateral plasma membrane ...formation of structure involved in a symbiotic process / positive regulation of nucleocytoplasmic transport / negative regulation of sodium ion transport / regulation of potassium ion transmembrane transporter activity / viral budding / nuclear receptor-mediated glucocorticoid signaling pathway / : / phosphothreonine residue binding / receptor catabolic process / apicolateral plasma membrane / protein targeting to lysosome / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / regulation of monoatomic ion transmembrane transport / HECT-type E3 ubiquitin transferase / proline-rich region binding / sodium channel inhibitor activity / RNA polymerase binding / beta-2 adrenergic receptor binding / lysosomal transport / regulation of dendrite morphogenesis / negative regulation of vascular endothelial growth factor receptor signaling pathway / neuromuscular junction development / regulation of synapse organization / phosphoserine residue binding / protein K63-linked ubiquitination / ubiquitin ligase complex / regulation of macroautophagy / progesterone receptor signaling pathway / Downregulation of ERBB4 signaling / Regulation of PTEN localization / ubiquitin binding / regulation of membrane potential / receptor internalization / ISG15 antiviral mechanism / Regulation of PTEN stability and activity / response to calcium ion / positive regulation of protein catabolic process / neuron projection development / ubiquitin-protein transferase activity / cellular response to UV / ubiquitin protein ligase activity / Antigen processing: Ubiquitination & Proteasome degradation / cell cortex / ubiquitin-dependent protein catabolic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein ubiquitination / protein domain specific binding / innate immune response / DNA damage response / chromatin / perinuclear region of cytoplasm / enzyme binding / negative regulation of transcription by RNA polymerase II / Golgi apparatus / protein-containing complex / extracellular exosome / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. ...: / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / WW domain / C2 domain superfamily
Similarity search - Domain/homology
: / E3 ubiquitin-protein ligase NEDD4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsCecatiello, V. / Maspero, E.
Funding support Italy, United Kingdom, 2items
OrganizationGrant numberCountry
Fondazione CARIPLO2017-0746 Italy
Worldwide Cancer Research19-0003 United Kingdom
CitationJournal: Commun Chem / Year: 2025
Title: Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4.
Authors: Maspero, E. / Cappa, A. / Weber, J. / Trifiro, P. / Amici, R. / Bruno, A. / Faga, G. / Cecatiello, V. / Fattori, R. / Leuzzi, B. / Taibi, V. / Meroni, G. / Pasi, M. / Romussi, A. / Sartori, ...Authors: Maspero, E. / Cappa, A. / Weber, J. / Trifiro, P. / Amici, R. / Bruno, A. / Faga, G. / Cecatiello, V. / Fattori, R. / Leuzzi, B. / Taibi, V. / Meroni, G. / Pasi, M. / Romussi, A. / Sartori, L. / Villa, M. / Vultaggio, S. / Ciro, M. / Soffientini, P. / Lombardo, L. / Dahe, S. / Bachi, A. / Varasi, M. / Rossi, M. / Pasqualato, S. / Mercurio, C. / Polo, S.
History
DepositionOct 31, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 4, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 4 of E3 ubiquitin-protein ligase NEDD4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2886
Polymers44,7391
Non-polymers5495
Water1,71195
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area750 Å2
ΔGint11 kcal/mol
Surface area19640 Å2
Unit cell
Length a, b, c (Å)175.750, 38.890, 60.070
Angle α, β, γ (deg.)90.00, 92.85, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Isoform 4 of E3 ubiquitin-protein ligase NEDD4 / Cell proliferation-inducing gene 53 protein / HECT-type E3 ubiquitin transferase NEDD4 / Neural ...Cell proliferation-inducing gene 53 protein / HECT-type E3 ubiquitin transferase NEDD4 / Neural precursor cell expressed developmentally down-regulated protein 4 / NEDD-4


Mass: 44739.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NEDD4, KIAA0093, NEDD4-1, RPF1, PIG53 / Production host: Escherichia coli (E. coli)
References: UniProt: P46934, HECT-type E3 ubiquitin transferase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-A1ITH / Norclomipramine / 3-(2-chloranyl-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N-methyl-propan-1-amine / Desmethylclomipramine


Mass: 300.826 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21ClN2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 2.29 Å3/Da / Density % sol: 46.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100 mM MES pH 6.0 8-10% PEG 400 20% glycerol 1-4 mM inhibitor (0.25-1% DMSO)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1.00002 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.12→60 Å / Num. obs: 23416 / % possible obs: 99.8 % / Redundancy: 3.7 % / Biso Wilson estimate: 38.6 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.04 / Net I/σ(I): 17.1
Reflection shellResolution: 2.12→2.18 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.519 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 1725 / CC1/2: 0.699 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIXdev_1839refinement
xia20.3.8.0data reduction
Aimless0.3.11data scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2xbf

2xbf


Resolution: 2.12→60 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2365 1194 5.1 %
Rwork0.1858 --
obs0.1885 23413 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.12→60 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3148 0 37 95 3280
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083280
X-RAY DIFFRACTIONf_angle_d1.0554414
X-RAY DIFFRACTIONf_dihedral_angle_d14.6451221
X-RAY DIFFRACTIONf_chiral_restr0.042441
X-RAY DIFFRACTIONf_plane_restr0.005567
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1201-2.20490.33981450.25122424X-RAY DIFFRACTION100
2.2049-2.30530.36041330.24712464X-RAY DIFFRACTION100
2.3053-2.42680.31091020.22462470X-RAY DIFFRACTION100
2.4268-2.57890.27491360.21972459X-RAY DIFFRACTION100
2.5789-2.7780.26681440.21382424X-RAY DIFFRACTION100
2.778-3.05760.33011170.21822470X-RAY DIFFRACTION100
3.0576-3.50.23651330.19372465X-RAY DIFFRACTION99
3.5-4.40940.20391420.16152489X-RAY DIFFRACTION100
4.4094-600.18721420.15262554X-RAY DIFFRACTION99
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)
11.4967-0.48590.57183.1465-0.44814.39810.08990.1729-0.0602-0.3558-0.0818-0.35010.01520.2309-0.02890.1936-0.05640.02150.2576-0.02390.3025-25.5867-24.6306-3.9435
22.1197-1.2893-1.88192.16261.69762.8759-0.0512-0.17950.17480.36650.0805-0.12810.05950.1375-0.02190.3179-0.0252-0.04020.2630.01110.2312-37.0374-18.888117.4021
36.3275-1.80771.72538.8262-0.20487.56210.13240.1320.2172-0.776-0.2859-0.7830.3321-0.29520.15730.48940.07690.09210.3980.00870.6174-1.6482-13.555613.6963
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 519 through 647 )
2X-RAY DIFFRACTION2chain 'A' and (resid 648 through 784 )
3X-RAY DIFFRACTION3chain 'A' and (resid 785 through 893 )

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