PMID- 16922504
OWN - NLM
STAT- MEDLINE
DCOM- 20061026
LR  - 20211203
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 45
IP  - 34
DP  - 2006 Aug 29
TI  - The FRB domain of mTOR: NMR solution structure and inhibitor design.
PG  - 10294-302
AB  - The mammalian target of rapamycin (mTOR) is a protein that is intricately 
      involved in signaling pathways controlling cell growth. Rapamycin is a natural 
      product that binds and inhibits mTOR function by interacting with its 
      FKBP-rapamycin-binding (FRB) domain. Here we report on the NMR solution structure 
      of FRB and on further studies aimed at the identification and characterization of 
      novel ligands that target the rapamycin binding pocket. The biological activity 
      of the ligands, and that of rapamycin in the absence of FKBP12, was investigated 
      by assaying the kinase activity of mTOR. While we found that rapamycin binds the 
      FRB domain and inhibits the kinase activity of mTOR even in the absence of FKBP12 
      (in the low micromolar range), our most potent ligands bind to FRB with similar 
      binding affinity but inhibit the kinase activity of mTOR at much higher 
      concentrations. However, we have also identified one low-affinity compound that 
      is also capable of inhibiting mTOR. Hence, we have identified compounds that can 
      directly mimic rapamycin or can dissociate the FRB binding from the inhibition of 
      the catalytic activity of mTOR. As such, these ligands could be useful in 
      deciphering the complex regulation of mTOR in the cell and in validating the FRB 
      domain as a possible target for the development of novel therapeutic compounds.
FAU - Leone, Marilisa
AU  - Leone M
AD  - Cancer Research Center, Burnham Institute for Medical Research, 10901 North 
      Torrey Pines Road, La Jolla, California 92037, USA.
FAU - Crowell, Kevin J
AU  - Crowell KJ
FAU - Chen, Jinhua
AU  - Chen J
FAU - Jung, Dawoon
AU  - Jung D
FAU - Chiang, Gary G
AU  - Chiang GG
FAU - Sareth, Sina
AU  - Sareth S
FAU - Abraham, Robert T
AU  - Abraham RT
FAU - Pellecchia, Maurizio
AU  - Pellecchia M
LA  - eng
SI  - PDB/2GAQ
GR  - CA052995/CA/NCI NIH HHS/United States
GR  - CA102583/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ligands)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *Drug Design
MH  - Enzyme Inhibitors/*chemistry/metabolism
MH  - Humans
MH  - Ligands
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Protein Binding
MH  - Protein Kinases/*chemistry/metabolism
MH  - Protein Structure, Tertiary
MH  - Signal Transduction/drug effects
MH  - Sirolimus/chemistry/metabolism
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/08/23 09:00
MHDA- 2006/10/27 09:00
CRDT- 2006/08/23 09:00
PHST- 2006/08/23 09:00 [pubmed]
PHST- 2006/10/27 09:00 [medline]
PHST- 2006/08/23 09:00 [entrez]
AID - 10.1021/bi060976+ [doi]
PST - ppublish
SO  - Biochemistry. 2006 Aug 29;45(34):10294-302. doi: 10.1021/bi060976+.