7RLG

Cryo-EM structure of human p97-D592N mutant bound to ADP.


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.70 Å
  • Aggregation State: 2D ARRAY 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

AAA+ ATPase p97/VCP mutants and inhibitor binding disrupt inter-domain coupling and subsequent allosteric activation.

Caffrey, B.Zhu, X.Berezuk, A.Tuttle, K.Chittori, S.Subramaniam, S.

(2021) J Biol Chem 297: 101187-101187

  • DOI: 10.1016/j.jbc.2021.101187
  • Primary Citation of Related Structures:  
    7RL6, 7RL7, 7RL9, 7RLA, 7RLB, 7RLC, 7RLD, 7RLF, 7RLG, 7RLH, 7RLI, 7RLJ

  • PubMed Abstract: 
  • The human AAA ATPase p97, a potential target for cancer therapeutics, plays a vital role in the clearing of misfolded proteins. p97 dysfunction is also known to play a crucial role in several neurodegenerative disorders, such as MultiSystem Proteinopathy 1 (MSP-1) and Familial Amyotrophic Lateral Sclerosis (ALS) ...

    The human AAA ATPase p97, a potential target for cancer therapeutics, plays a vital role in the clearing of misfolded proteins. p97 dysfunction is also known to play a crucial role in several neurodegenerative disorders, such as MultiSystem Proteinopathy 1 (MSP-1) and Familial Amyotrophic Lateral Sclerosis (ALS). However, the structural basis of its role in such diseases remain elusive. Here, we present cryo-EM structural analyses of four disease mutants p97R155H, p97R191Q, p97A232E, p97D592N, as well as p97E470D, implicated in resistance to the drug CB-5083, a potent p97 inhibitor. Our cryo-EM structures demonstrate that these mutations affect nucleotide-driven allosteric activation across the three principal p97 domains (N, D1 and D2) by predominantly interfering with either 1) the coupling between the D1 and N-terminal domains (p97R155H and p97R191Q), 2) the inter-protomer interactions (p97A232E), or 3) the coupling between D1 and D2 nucleotide domains (p97D592N, p97E470D). We also show that binding of the competitive inhibitor, CB-5083, to the D2 domain prevents conformational changes similar to those seen for mutations that affect coupling between the D1 and D2 domains. Our studies enable tracing of the path of allosteric activation across p97 and establish a common mechanistic link between active site inhibition and defects in allosteric activation by disease-causing mutations, and have potential implications for the design of novel allosteric compounds that can modulate p97 function.


    Organizational Affiliation

    Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: sriram.subramaniam@ubc.ca.



Macromolecules
Find similar proteins by:  (by identity cutoff)  |  Structure
Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Transitional endoplasmic reticulum ATPaseA, B, C, D, E, F821Homo sapiensMutation(s): 1 
Gene Names: VCP
EC: 3.6.4.6
UniProt & NIH Common Fund Data Resources
Find proteins for P55072 (Homo sapiens)
Explore P55072 
Go to UniProtKB:  P55072
PHAROS:  P55072
Protein Feature View
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.70 Å
  • Aggregation State: 2D ARRAY 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report




Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-09-22
    Type: Initial release
  • Version 1.1: 2021-09-29
    Changes: Database references
  • Version 1.2: 2021-11-17
    Changes: Database references