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- PDB-7ujd: PSMD2 Structure bound to MC1 and Fab8/14 -

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Basic information

Entry
Database: PDB / ID: 7ujd
TitlePSMD2 Structure bound to MC1 and Fab8/14
Components
  • 26S proteasome non-ATPase regulatory subunit 2
  • ACY-PHE-PRO-ASP-VAL-SAR-LEU-HIS-ARG-TYR-TRP-GLY-TRP-ASP-CYS-GLY-NH2
  • Fab 14 HC CDRs
  • Fab 14 LC CDRs
  • Fab 8 HC CDRs
  • Fab 8 LC CDRs
KeywordsPROTEIN BINDING/Immune System / 26S proteasome macrocycle / PROTEIN BINDING / PROTEIN BINDING-Immune System complex
Function / homology
Function and homology information


proteasome accessory complex / proteasome regulatory particle / proteasome regulatory particle, base subcomplex / Regulation of ornithine decarboxylase (ODC) / Proteasome assembly / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / regulation of protein catabolic process / proteasome storage granule / enzyme regulator activity ...proteasome accessory complex / proteasome regulatory particle / proteasome regulatory particle, base subcomplex / Regulation of ornithine decarboxylase (ODC) / Proteasome assembly / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / regulation of protein catabolic process / proteasome storage granule / enzyme regulator activity / proteasome complex / Regulation of activated PAK-2p34 by proteasome mediated degradation / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / TNFR2 non-canonical NF-kB pathway / AUF1 (hnRNP D0) binds and destabilizes mRNA / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Degradation of DVL / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Degradation of AXIN / Hh mutants are degraded by ERAD / Activation of NF-kappaB in B cells / Degradation of GLI1 by the proteasome / G2/M Checkpoints / Hedgehog ligand biogenesis / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Defective CFTR causes cystic fibrosis / Autodegradation of the E3 ubiquitin ligase COP1 / Negative regulation of NOTCH4 signaling / Regulation of RUNX3 expression and activity / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / MAPK6/MAPK4 signaling / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / ABC-family proteins mediated transport / CDK-mediated phosphorylation and removal of Cdc6 / CLEC7A (Dectin-1) signaling / SCF(Skp2)-mediated degradation of p27/p21 / FCERI mediated NF-kB activation / Regulation of expression of SLITs and ROBOs / Regulation of PTEN stability and activity / Interleukin-1 signaling / Orc1 removal from chromatin / Regulation of RAS by GAPs / Regulation of RUNX2 expression and activity / The role of GTSE1 in G2/M progression after G2 checkpoint / Separation of Sister Chromatids / KEAP1-NFE2L2 pathway / UCH proteinases / Downstream TCR signaling / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / ER-Phagosome pathway / secretory granule lumen / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / Ub-specific processing proteases / Neutrophil degranulation / extracellular exosome / extracellular region / nucleoplasm / nucleus / membrane / cytosol
Similarity search - Function
26S proteasome regulatory complex, non-ATPase subcomplex, Rpn1 subunit / RPN1, N-terminal / 26S proteasome non-ATPase regulatory subunit RPN1, C-terminal / RPN1 N-terminal domain / 26S proteasome non-ATPase regulatory subunit RPN1 C-terminal / Proteasome/cyclosome repeat / Proteasome/cyclosome repeat / Leucine-rich Repeat Variant / Leucine-rich Repeat Variant / Armadillo-like helical ...26S proteasome regulatory complex, non-ATPase subcomplex, Rpn1 subunit / RPN1, N-terminal / 26S proteasome non-ATPase regulatory subunit RPN1, C-terminal / RPN1 N-terminal domain / 26S proteasome non-ATPase regulatory subunit RPN1 C-terminal / Proteasome/cyclosome repeat / Proteasome/cyclosome repeat / Leucine-rich Repeat Variant / Leucine-rich Repeat Variant / Armadillo-like helical / Alpha Horseshoe / Armadillo-type fold / Mainly Alpha
Similarity search - Domain/homology
26S proteasome non-ATPase regulatory subunit 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsJohnson, M.C. / Bashore, C. / Ciferri, C. / Dueber, E.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Chem Biol / Year: 2023
Title: Targeted degradation via direct 26S proteasome recruitment.
Authors: Charlene Bashore / Sumit Prakash / Matthew C Johnson / Ryan J Conrad / Ivy A Kekessie / Suzie J Scales / Noriko Ishisoko / Tracy Kleinheinz / Peter S Liu / Nataliya Popovych / Aaron T ...Authors: Charlene Bashore / Sumit Prakash / Matthew C Johnson / Ryan J Conrad / Ivy A Kekessie / Suzie J Scales / Noriko Ishisoko / Tracy Kleinheinz / Peter S Liu / Nataliya Popovych / Aaron T Wecksler / Lijuan Zhou / Christine Tam / Inna Zilberleyb / Rajini Srinivasan / Robert A Blake / Aimin Song / Steven T Staben / Yingnan Zhang / David Arnott / Wayne J Fairbrother / Scott A Foster / Ingrid E Wertz / Claudio Ciferri / Erin C Dueber /
Abstract: Engineered destruction of target proteins by recruitment to the cell's degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted ...Engineered destruction of target proteins by recruitment to the cell's degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted degradation do so via a select number of ubiquitin ligases, restricting this therapeutic approach to tissue types that express the requisite ligase. Here, we describe a new strategy of targeted protein degradation through direct substrate recruitment to the 26S proteasome. The proteolytic complex is essential and abundantly expressed in all cells; however, proteasomal ligands remain scarce. We identify potent peptidic macrocycles that bind directly to the 26S proteasome subunit PSMD2, with a 2.5-Å-resolution cryo-electron microscopy complex structure revealing a binding site near the 26S pore. Conjugation of this macrocycle to a potent BRD4 ligand enabled generation of chimeric molecules that effectively degrade BRD4 in cells, thus demonstrating that degradation via direct proteasomal recruitment is a viable strategy for targeted protein degradation.
History
DepositionMar 30, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 26S proteasome non-ATPase regulatory subunit 2
C: Fab 14 LC CDRs
D: Fab 14 HC CDRs
E: Fab 8 LC CDRs
F: Fab 8 HC CDRs
Z: ACY-PHE-PRO-ASP-VAL-SAR-LEU-HIS-ARG-TYR-TRP-GLY-TRP-ASP-CYS-GLY-NH2


Theoretical massNumber of molelcules
Total (without water)168,9026
Polymers168,9026
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Antibody , 4 types, 4 molecules CDEF

#2: Antibody Fab 14 LC CDRs


Mass: 23825.389 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Fab 14 HC CDRs


Mass: 24717.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Antibody Fab 8 LC CDRs


Mass: 23689.238 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#5: Antibody Fab 8 HC CDRs


Mass: 24606.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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Protein / Protein/peptide , 2 types, 2 molecules AZ

#1: Protein 26S proteasome non-ATPase regulatory subunit 2 / 26S proteasome regulatory subunit RPN1 / 26S proteasome regulatory subunit S2 / 26S proteasome ...26S proteasome regulatory subunit RPN1 / 26S proteasome regulatory subunit S2 / 26S proteasome subunit p97 / Protein 55.11 / Tumor necrosis factor type 1 receptor-associated protein 2


Mass: 70199.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PSMD2, TRAP2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13200
#6: Protein/peptide ACY-PHE-PRO-ASP-VAL-SAR-LEU-HIS-ARG-TYR-TRP-GLY-TRP-ASP-CYS-GLY-NH2


Mass: 1864.071 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: PSMD2 bound to MC1 and Fab8/14 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 3000 nm / Nominal defocus min: 300 nm
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105705 / Symmetry type: POINT

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