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- PDB-9f19: Human USP30 chimera in complex with NK036 inhibitor -

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Basic information

Entry
Database: PDB / ID: 9f19
TitleHuman USP30 chimera in complex with NK036 inhibitor
ComponentsUbiquitin carboxyl-terminal hydrolase 30,Ubiquitin carboxyl-terminal hydrolase 14,Ubiquitin carboxyl-terminal hydrolase 35
KeywordsHYDROLASE / USP30 / Ubiquitin / inhibitor / DUB / deubiquitinating enzyme / USP14 / USP35 / mitophagy / USP / Ubiquitin-specific protease / Ubiquitin carboxyl-terminal hydrolase 30 / Compound 39 / Sulfonamide / Phenylalanine
Function / homology
Function and homology information


protein K6-linked deubiquitination / protein K11-linked deubiquitination / negative regulation of ERAD pathway / regulation of chemotaxis / deubiquitinase activity / protein K48-linked deubiquitination / autophagy of mitochondrion / pexophagy / peroxisomal membrane / mitochondrial fusion ...protein K6-linked deubiquitination / protein K11-linked deubiquitination / negative regulation of ERAD pathway / regulation of chemotaxis / deubiquitinase activity / protein K48-linked deubiquitination / autophagy of mitochondrion / pexophagy / peroxisomal membrane / mitochondrial fusion / endopeptidase inhibitor activity / K63-linked deubiquitinase activity / negative regulation of mitophagy / proteasome binding / negative regulation of ubiquitin-dependent protein catabolic process / protein deubiquitination / presynaptic cytosol / regulation of proteasomal protein catabolic process / proteasome complex / Pexophagy / Regulation of NF-kappa B signaling / regulation of protein stability / cytoplasmic vesicle / chemical synaptic transmission / proteasome-mediated ubiquitin-dependent protein catabolic process / mitochondrial outer membrane / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Ub-specific processing proteases / innate immune response / cysteine-type endopeptidase activity / nucleolus / glutamatergic synapse / cell surface / endoplasmic reticulum / mitochondrion / proteolysis / extracellular exosome / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Ubiquitin carboxyl-terminal hydrolase 38-like, N-terminal domain / Ubiquitin carboxyl-terminal hydrolase 14-like / : / Ubiquitin specific protease (USP) domain signature 2. / Ubiquitin specific protease (USP) domain signature 1. / Ubiquitin specific protease, conserved site / Peptidase C19, ubiquitin carboxyl-terminal hydrolase / Ubiquitin carboxyl-terminal hydrolase / Ubiquitin specific protease domain ...: / Ubiquitin carboxyl-terminal hydrolase 38-like, N-terminal domain / Ubiquitin carboxyl-terminal hydrolase 14-like / : / Ubiquitin specific protease (USP) domain signature 2. / Ubiquitin specific protease (USP) domain signature 1. / Ubiquitin specific protease, conserved site / Peptidase C19, ubiquitin carboxyl-terminal hydrolase / Ubiquitin carboxyl-terminal hydrolase / Ubiquitin specific protease domain / Ubiquitin specific protease (USP) domain profile. / Papain-like cysteine peptidase superfamily / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
: / Ubiquitin carboxyl-terminal hydrolase 14 / Ubiquitin carboxyl-terminal hydrolase 30 / Ubiquitin carboxyl-terminal hydrolase 35
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsKazi, N.H. / Gersch, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
Max Planck SocietyCGCIII-352S Germany
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2025
Title: Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
Authors: Kazi, N.H. / Klink, N. / Gallant, K. / Kipka, G.M. / Gersch, M.
History
DepositionApr 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
Revision 1.1May 14, 2025Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _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 30,Ubiquitin carboxyl-terminal hydrolase 14,Ubiquitin carboxyl-terminal hydrolase 35
B: Ubiquitin carboxyl-terminal hydrolase 30,Ubiquitin carboxyl-terminal hydrolase 14,Ubiquitin carboxyl-terminal hydrolase 35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,2804
Polymers72,2532
Non-polymers1,0272
Water1,24369
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area960 Å2
ΔGint-4 kcal/mol
Surface area22950 Å2
Unit cell
Length a, b, c (Å)55.833, 73.835, 201.053
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Space group name HallP22ab(y,z,x)
Symmetry operation#1: x,y,z
#2: x+1/2,-y,-z+1/2
#3: -x,y,-z
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Ubiquitin carboxyl-terminal hydrolase 30,Ubiquitin carboxyl-terminal hydrolase 14,Ubiquitin carboxyl-terminal hydrolase 35 / Deubiquitinating enzyme 30 / Ubiquitin thioesterase 30 / Ubiquitin-specific-processing protease 30 ...Deubiquitinating enzyme 30 / Ubiquitin thioesterase 30 / Ubiquitin-specific-processing protease 30 / Ub-specific protease 30 / Deubiquitinating enzyme 14 / Ubiquitin thioesterase 14 / Ubiquitin-specific-processing protease 14 / Deubiquitinating enzyme 35 / Ubiquitin thioesterase 35 / Ubiquitin-specific-processing protease 35


Mass: 36126.668 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35) ...Details: Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35),Human USP30 (chimera with parts of human USP14 and human USP35)
Source: (gene. exp.) Homo sapiens (human) / Gene: USP30, USP14, TGT, USP35, KIAA1372, USP34 / Production host: Escherichia coli (E. coli)
References: UniProt: Q70CQ3, UniProt: P54578, UniProt: Q9P2H5, ubiquitinyl hydrolase 1
#2: Chemical ChemComp-A1H8X / 4-fluoranyl-~{N}-[(2~{S})-1-[[4-[(2-methyl-1-oxidanyl-propan-2-yl)sulfamoyl]phenyl]amino]-1-oxidanylidene-3-phenyl-propan-2-yl]benzamide / NK036 USP30 inhibitor


Mass: 513.581 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28FN3O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 3

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Sample preparation

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
12.8757.11
2
3
Crystal grow
Temperature (K)Crystal-IDMethodDetails
2931vapor diffusion, sitting drop76 mM NaOH, 100 mM Bicine, 10.2% (w/v) PEG 20,000, 1% (v/v) Dioxane, 10 mM L-Proline (Crystal 1)
2932vapor diffusion, sitting drop85 mM NaOH, 100 mM Bicine, 10.2% (w/v) PEG 20,000, 1% (v/v) Dioxane, 10 mM L-Proline (Crystal 2)
2933vapor diffusion, sitting drop88 mM NaOH, 100 mM Bicine, 11% (w/v) PEG 20,000, 1% (v/v) Dioxane, 10 mM Sarcosine (Crystal 3)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Nov 16, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 2.75→59.52 Å / Num. obs: 15438 / % possible obs: 91.9 % / Redundancy: 13.9 % / Biso Wilson estimate: 78.31 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.166 / Net I/σ(I): 9.6
Reflection shellResolution: 2.75→3.23 Å / Redundancy: 13.9 % / Rmerge(I) obs: 1.536 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 2202 / CC1/2: 0.73 / % possible all: 69

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Processing

Software
NameVersionClassification
xia23.16.0data reduction
DIALS3.16.0-ga309fad1d-releasedata reduction
STARANISO3.35data scaling
PHASER2.8.3phasing
Coot0.9.8.92model building
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→59.51 Å / SU ML: 0.2898 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.8132
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2661 1543 10 %
Rwork0.2181 13889 -
obs0.2229 15432 68.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 79.2 Å2
Refinement stepCycle: LAST / Resolution: 2.75→59.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3791 0 72 69 3932
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083957
X-RAY DIFFRACTIONf_angle_d1.09075397
X-RAY DIFFRACTIONf_chiral_restr0.0549618
X-RAY DIFFRACTIONf_plane_restr0.0093678
X-RAY DIFFRACTIONf_dihedral_angle_d17.60041302
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.840.445790.38976X-RAY DIFFRACTION4.27
2.84-2.940.3983300.3498279X-RAY DIFFRACTION15.4
2.94-3.060.3724600.3525540X-RAY DIFFRACTION30.49
3.06-3.20.3773990.3112882X-RAY DIFFRACTION48.61
3.2-3.360.3411320.28511193X-RAY DIFFRACTION66.58
3.36-3.570.29511730.2541565X-RAY DIFFRACTION86.38
3.58-3.850.27642040.21971827X-RAY DIFFRACTION99.56
3.85-4.240.25922030.1931825X-RAY DIFFRACTION99.85
4.24-4.850.21822050.15961849X-RAY DIFFRACTION99.9
4.85-6.110.25042090.19971877X-RAY DIFFRACTION99.9
6.11-59.510.26842190.24371976X-RAY DIFFRACTION99.77
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)
15.741086391270.0197615527995-1.152411522312.483865549890.9849843714634.3247178201-0.0409949400693-0.195805235268-0.544844018425-0.0466272080822-0.05361786561730.07399790498320.6552625335170.1189584492290.04108414756240.638158521517-0.0804223592105-0.02614428915320.2346163826240.09327466164760.39874507280212.4007814679-16.4710774449-43.5697535427
22.7658178427-0.444670171527-0.8634838902793.683175238421.576015987347.71087868822-0.243242635732-0.524304282607-0.133877283893-0.277099098494-0.1181920241360.12826703356-0.543260122692-0.5258650237190.2691922523310.363906357158-0.0547307611727-0.0514785632780.746080390063-0.01168283673670.355898378713-5.384817060974.32399653005-20.1884668485
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'A' and resid 66 through 601)AA - B66 - 6011
22(chain 'B' and resid 64 through 502)BC64 - 5021 - 252

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