PMID- 23619386
OWN - NLM
STAT- MEDLINE
DCOM- 20130911
LR  - 20211203
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Linking)
VI  - 84
IP  - 1
DP  - 2013 Jul
TI  - Rapamycin allosterically inhibits the proteasome.
PG  - 104-13
LID - 10.1124/mol.112.083873 [doi]
AB  - Rapamycin is a canonical allosteric inhibitor of the mammalian tarpet of 
      rapamycin (mTOR) kinase with immunosuppressive and proapoptotic activities. We 
      found that in vitro rapamycin also regulates the proteasome, which is an 
      essential intracellular protease of the ubiquitin-proteasome pathway. Rapamycin 
      inhibits proteinase and selected peptidase activities of the catalytic core 
      proteasome at low micromolar concentrations. Moreover, the drug interferes with 
      binding of the 19S cap essential for processing of polyubiquitinylated substrates 
      and with the PA200 proteasome activator to the 20S catalytic core proteasome. 
      These protein complexes are known to bind to specific grooves on the alpha face 
      region of the 20S core. Treatment with rapamycin affects the conformational 
      dynamics of the proteasomal gate, which is centrally positioned within the alpha face 
      and allosterically regulated element responsible for the intake of substrates. We 
      showed that rapamycin shares all the proteasome targeting properties not only 
      with other two-domain, closed-ring analogs (rapalogs) but also with its single 
      domain mimics and seco-rapamycin, which is the first in vivo open-ring metabolite 
      of rapamycin that does not affect mTOR. We hypothesize that rapamycin and related 
      compounds bind to the alpha face and allosterically impact proteasome function. This 
      article discusses the implications of our findings for the mechanism of in vivo 
      actions of rapamycin and for the design of novel allosteric drugs targeting the 
      proteasome.
FAU - Osmulski, Pawel A
AU  - Osmulski PA
AD  - University of Texas Health Science Center at San Antonio, Department of Molecular 
      Medicine, Institute of Biotechnology, 15355 Lambda Drive, San Antonio, TX 78245, 
      USA.
FAU - Gaczynska, Maria
AU  - Gaczynska M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130425
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Ubiquitin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Allosteric Regulation
MH  - Catalytic Domain
MH  - Humans
MH  - Peptide Hydrolases/metabolism
MH  - Proteasome Endopeptidase Complex/chemistry/*metabolism
MH  - Proteasome Inhibitors/*pharmacology
MH  - Protein Binding
MH  - Protein Conformation
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Ubiquitin/metabolism
EDAT- 2013/04/27 06:00
MHDA- 2013/09/12 06:00
CRDT- 2013/04/27 06:00
PHST- 2013/04/27 06:00 [entrez]
PHST- 2013/04/27 06:00 [pubmed]
PHST- 2013/09/12 06:00 [medline]
AID - mol.112.083873 [pii]
AID - 10.1124/mol.112.083873 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2013 Jul;84(1):104-13. doi: 10.1124/mol.112.083873. Epub 2013 Apr 
      25.