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TitleAAA+ ATPase p97/VCP mutants and inhibitor binding disrupt inter-domain coupling and subsequent allosteric activation.
Journal, issue, pagesJ Biol Chem, Vol. 297, Issue 4, Page 101187, Year 2021
Publish dateSep 11, 2021
AuthorsBrian Caffrey / Xing Zhu / Alison Berezuk / Katharine Tuttle / Sagar Chittori / Sriram Subramaniam /
PubMed AbstractThe human AAA+ ATPase p97, also known as valosin-containing protein, a potential target for cancer therapeutics, plays a vital role in the clearing of misfolded proteins. p97 dysfunction is also ...The human AAA+ ATPase p97, also known as valosin-containing protein, 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 remains elusive. Here, we present cryo-EM structural analyses of four disease mutants p97, p97, p97, p97, as well as p97, 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 (p97 and p97), (2) the interprotomer interactions (p97), or (3) the coupling between D1 and D2 nucleotide domains (p97, p97). 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.
External linksJ Biol Chem / PubMed:34520757 / PubMed Central
MethodsEM (single particle)
Resolution3 - 3.8 Å
Structure data

EMDB-24518, PDB-7rl6:
Cryo-EM structure of human p97-R155H mutant bound to ADP.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-24519, PDB-7rl7:
Cryo-EM structure of human p97-R155H mutant bound to ATPgS.
Method: EM (single particle) / Resolution: 3 Å

EMDB-24522, PDB-7rl9:
Cryo-EM structure of human p97-R191Q mutant bound to ADP.
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-24523, PDB-7rla:
Cryo-EM structure of human p97-R191Q mutant bound to ATPgS.
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-24524, PDB-7rlb:
Cryo-EM structure of human p97-A232E mutant bound to ADP
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-24525, PDB-7rlc:
Cryo-EM structure of human p97-A232E mutant bound to ATPgS.
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-24526, PDB-7rld:
Cryo-EM structure of human p97-E470D mutant bound to ADP.
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-24528, PDB-7rlf:
Cryo-EM structure of human p97-E470D mutant bound to ATPgS.
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-24529, PDB-7rlg:
Cryo-EM structure of human p97-D592N mutant bound to ADP.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-24530, PDB-7rlh:
Cryo-EM structure of human p97-D592N mutant bound to ATPgS.
Method: EM (single particle) / Resolution: 3 Å

EMDB-24531, PDB-7rli:
Cryo-EM structure of human p97 bound to CB-5083 and ADP.
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-24532, PDB-7rlj:
Cryo-EM structure of human p97 bound to CB-5083 and ATPgS.
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-JDP:
1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide

Source
  • homo sapiens (human)
KeywordsHYDROLASE / p97 / VCP / TERA / Inhibitor / CB-5083

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