[English] 日本語
Yorodumi
- PDB-9p02: Cryo-EM structure of S. Mansoni p97 bound to compound 739 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 9p02
TitleCryo-EM structure of S. Mansoni p97 bound to compound 739
Componentsvesicle-fusing ATPase
KeywordsCHAPERONE / AAA-ATPase / Endoplasmic Reticulum / Hexamer / Inhibitor
Function / homology
Function and homology information


mitotic spindle disassembly / VCP-NPL4-UFD1 AAA ATPase complex / vesicle-fusing ATPase / retrograde protein transport, ER to cytosol / polyubiquitin modification-dependent protein binding / autophagosome maturation / ATP hydrolysis activity / ATP binding / nucleus / cytosol
Similarity search - Function
AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48), domain 2 / Cell division protein 48 (CDC48) domain 2 / : / CDC48 domain 2-like superfamily / Aspartate decarboxylase-like domain superfamily ...AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48), domain 2 / Cell division protein 48 (CDC48) domain 2 / : / CDC48 domain 2-like superfamily / Aspartate decarboxylase-like domain superfamily / AAA ATPase, AAA+ lid domain / AAA+ lid domain / ATPase, AAA-type, conserved site / AAA-protein family signature. / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / vesicle-fusing ATPase
Similarity search - Component
Biological speciesSchistosoma mansoni (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsStephens, D.R. / Han, Y. / Chen, Z. / Liang, J. / Ready, J. / Collins, J.J. / Fung, H.Y.J.
Funding support United States, 5items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RP220582 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI167967 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI150776 United States
Welch FoundationI-1948-20240404 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site in .
Authors: Dylon R Stephens / Ho Yee Joyce Fung / Yan Han / Jue Liang / Zhe Chen / Joseph Ready / James J Collins /
Abstract: Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within ...Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within schistosomes. Thus, praziquantel has remained the frontline treatment for schistosomiasis despite known liabilities. Here, we have conducted a genome-wide study in using the human druggable genome as a bioinformatic template to identify essential genes within schistosomes bearing similarity to catalogued drug targets. Then, we assessed these candidate targets in silico using a set of unbiased criteria to determine which possess ideal characteristics for a ready-made drug discovery campaign. Following this prioritization, we pursued a parasite p97 ortholog as a bona-fide drug target for the development of therapeutics to treat schistosomiasis. From this effort, we identified a covalent inhibitor series that kills schistosomes through an on-target killing mechanism by disrupting the ubiquitin proteasome system. Fascinatingly, these inhibitors induce a conformational change in the conserved D2 domain P-loop of schistosome p97 upon modification of Cys519. This conformational change reveals an allosteric binding site adjacent to the D2 domain active site reminiscent of the "DFG" flip in protein kinases. This allosteric binding site can potentially be utilized to generate new classes of species-selective p97 inhibitors. Furthermore, these studies provide a resource for the development of alternative therapeutics for schistosomiasis and a workflow to identify potential drug targets in similar systems with few available molecular tools.
History
DepositionJun 6, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: vesicle-fusing ATPase
C: vesicle-fusing ATPase
D: vesicle-fusing ATPase
F: vesicle-fusing ATPase
B: vesicle-fusing ATPase
E: vesicle-fusing ATPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)558,58812
Polymers556,5346
Non-polymers2,0546
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

-
Components

#1: Protein
vesicle-fusing ATPase


Mass: 92755.594 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Details: First 37 residues are expression tags. / Source: (gene. exp.) Schistosoma mansoni (invertebrata) / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: G4M0P7, vesicle-fusing ATPase
#2: Chemical
ChemComp-A1CGC / (2E)-3-(pyridin-4-yl)-N-[2-(pyridin-2-yl)-1,3-benzoxazol-5-yl]prop-2-enamide


Mass: 342.351 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C20H14N4O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: Hexamer of p97 conjugated to inhibitor 739 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Schistosoma mansoni (invertebrata)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3)
Buffer solutionpH: 7.4
Details: 20mM Tris (pH 7.4), 180mM NaCl, 5mM MgCl2, and 1mM tris(2-carboxyethyl)phosphine (TCEP)
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

-
Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV

-
Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
8Cootmodel fitting
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
14PHENIX1.21_5207model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2812039
Details: Template pick with templates generated used the CB-5083-bound map
SymmetryPoint symmetry: C6 (6 fold cyclic)
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101602
Details: Non-uniform refinement with C6 symmetry applied, with global and CTF refinements. Unsharpened map was used for modeling
Symmetry type: POINT
Atomic model buildingDetails: Apo structure was docked as initial model, then went through multiple rounds of manual fitting in coot and refinement in Phenix.
Atomic model buildingPDB-ID: 9P00

9p00


Accession code: 9P00 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.06 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00525102
ELECTRON MICROSCOPYf_angle_d0.49733855
ELECTRON MICROSCOPYf_dihedral_angle_d3.6063429
ELECTRON MICROSCOPYf_chiral_restr0.0413803
ELECTRON MICROSCOPYf_plane_restr0.0054480

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more