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- PDB-8f1f: Structure of K48-linked tri-ubiquitin in complex with cyclic peptide -

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Basic information

Entry
Database: PDB / ID: 8f1f
TitleStructure of K48-linked tri-ubiquitin in complex with cyclic peptide
Components
  • (Ubiquitin) x 3
  • Non-proteinogenic cyclic peptide (inhibitor)
KeywordsSIGNALING PROTEIN / complex / therapeutic peptide / Lys48-linked polyubiquitin / macrocyclic peptide / inhibitor of ubiquitin signaling
Function / homology
Function and homology information


hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / fat pad development / mitochondrion transport along microtubule / female gonad development / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / energy homeostasis ...hypothalamus gonadotrophin-releasing hormone neuron development / female meiosis I / positive regulation of protein monoubiquitination / fat pad development / mitochondrion transport along microtubule / female gonad development / seminiferous tubule development / male meiosis I / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / energy homeostasis / regulation of neuron apoptotic process / regulation of proteasomal protein catabolic process / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / APC-Cdc20 mediated degradation of Nek2A / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Regulation of innate immune responses to cytosolic DNA / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / Regulation of PTEN localization / VLDLR internalisation and degradation / Activated NOTCH1 Transmits Signal to the Nucleus / neuron projection morphogenesis / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / regulation of mitochondrial membrane potential / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / Translesion synthesis by POLK / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / InlB-mediated entry of Listeria monocytogenes into host cell / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Translesion synthesis by POLI / Regulation of activated PAK-2p34 by proteasome mediated degradation / positive regulation of protein ubiquitination / IKK complex recruitment mediated by RIP1 / Gap-filling DNA repair synthesis and ligation in GG-NER / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / TCF dependent signaling in response to WNT / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / activated TAK1 mediates p38 MAPK activation / Negative regulators of DDX58/IFIH1 signaling / TNFR2 non-canonical NF-kB pathway / AUF1 (hnRNP D0) binds and destabilizes mRNA / Regulation of signaling by CBL / NOTCH3 Activation and Transmission of Signal to the Nucleus / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Degradation of DVL / Deactivation of the beta-catenin transactivating complex / Negative regulation of FGFR3 signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Dectin-1 mediated noncanonical NF-kB signaling / Fanconi Anemia Pathway / Peroxisomal protein import / Degradation of AXIN / Regulation of TNFR1 signaling / Negative regulation of FGFR2 signaling
Similarity search - Function
: / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å
AuthorsLubkowski, J. / Fushman, D. / Lemma, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM065334 United States
CitationJournal: Nat Commun / Year: 2023
Title: Mechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation.
Authors: Lemma, B. / Zhang, D. / Vamisetti, G.B. / Wentz, B.G. / Suga, H. / Brik, A. / Lubkowski, J. / Fushman, D.
History
DepositionNov 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _struct_conn.pdbx_leaving_atom_flag
Revision 1.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ubiquitin
B: Ubiquitin
C: Ubiquitin
a: Ubiquitin
b: Ubiquitin
c: Ubiquitin
1: Non-proteinogenic cyclic peptide (inhibitor)
2: Non-proteinogenic cyclic peptide (inhibitor)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,29111
Polymers54,7238
Non-polymers5693
Water5,386299
1
A: Ubiquitin
B: Ubiquitin
C: Ubiquitin
1: Non-proteinogenic cyclic peptide (inhibitor)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6926
Polymers27,3614
Non-polymers3302
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
a: Ubiquitin
b: Ubiquitin
c: Ubiquitin
2: Non-proteinogenic cyclic peptide (inhibitor)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6005
Polymers27,3614
Non-polymers2381
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)83.211, 26.963, 110.466
Angle α, β, γ (deg.)90.00, 99.85, 90.00
Int Tables number3
Space group name H-MP121

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Components

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Protein , 3 types, 6 molecules AaBbCc

#1: Protein Ubiquitin


Mass: 8691.918 Da / Num. of mol.: 2 / Mutation: D77 added to the C-terminus
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P0CG47
#2: Protein Ubiquitin


Mass: 8576.831 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47
#3: Protein Ubiquitin


Mass: 8604.845 Da / Num. of mol.: 2 / Mutation: K48R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47

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Protein/peptide , 1 types, 2 molecules 12

#4: Protein/peptide Non-proteinogenic cyclic peptide (inhibitor)


Mass: 1487.743 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli BL21(DE3) (bacteria)

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Non-polymers , 3 types, 302 molecules

#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.18 Å3/Da / Density % sol: 43.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Droplets were formed by mixing equal volumes of Ub3:Ub4a complex (8 mg/ml) and the crystallization solution containing 0.15 M NaCl, 23% (w/v) PEG 3350 and 0.1 M HEPES (pH 7.5)
PH range: 7.3-7.7 / Temp details: incubated in Rock Imager TI1000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→40 Å / Num. obs: 39731 / % possible obs: 93.8 % / Redundancy: 3.1 % / CC1/2: 0.987 / CC star: 0.997 / Rpim(I) all: 0.061 / Rrim(I) all: 0.113 / Rsym value: 0.062 / Net I/σ(I): 17.3
Reflection shellResolution: 1.85→1.88 Å / Redundancy: 3.2 % / Num. unique obs: 2070 / CC1/2: 0.907 / CC star: 0.975 / Rpim(I) all: 0.263 / Rrim(I) all: 0.493 / Rsym value: 0.375 / % possible all: 98.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ubq, monomer A

1ubq


Resolution: 1.85→30 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.889 / SU B: 4.003 / SU ML: 0.122 / Cross valid method: THROUGHOUT / ESU R: 0.196 / ESU R Free: 0.191 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29813 1986 5 %RANDOM
Rwork0.22787 ---
obs0.23137 37740 93.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.267 Å2
Baniso -1Baniso -2Baniso -3
1--0.94 Å2-0 Å21.27 Å2
2--0.59 Å20 Å2
3----0.08 Å2
Refinement stepCycle: 1 / Resolution: 1.85→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3828 0 36 299 4163
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0193934
X-RAY DIFFRACTIONr_bond_other_d0.0020.023847
X-RAY DIFFRACTIONr_angle_refined_deg2.1072.0285308
X-RAY DIFFRACTIONr_angle_other_deg1.11338972
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.025464
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.25625.26173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.04615762
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.911526
X-RAY DIFFRACTIONr_chiral_restr0.1330.2622
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214229
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02714
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.941.7721902
X-RAY DIFFRACTIONr_mcbond_other1.9411.7731899
X-RAY DIFFRACTIONr_mcangle_it2.7552.6452364
X-RAY DIFFRACTIONr_mcangle_other2.7552.6452364
X-RAY DIFFRACTIONr_scbond_it2.9962.1982032
X-RAY DIFFRACTIONr_scbond_other2.992.1982032
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.6233.1422941
X-RAY DIFFRACTIONr_long_range_B_refined6.44122.5014182
X-RAY DIFFRACTIONr_long_range_B_other6.38822.3134142
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 133 -
Rwork0.248 2841 -
obs--95.69 %

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