PMID- 17684489
OWN - NLM
STAT- MEDLINE
DCOM- 20080422
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 27
IP  - 5
DP  - 2008 Jan 24
TI  - Structural characterization of the interaction of mTOR with phosphatidic acid and 
      a novel class of inhibitor: compelling evidence for a central role of the FRB 
      domain in small molecule-mediated regulation of mTOR.
PG  - 585-95
AB  - The mammalian target of rapamycin (mTOR) is a large, multidomain protein kinase, 
      which plays a central role in the regulation of cell growth and has recently 
      emerged as an essential target of survival signals in many types of human cancer 
      cells. Here, we report the solution structures of complexes formed between the 
      FKBP12-rapamycin binding (FRB) domain of mTOR and phosphatidic acid, an important 
      cellular activator of the kinase, and between the FRB domain and a novel 
      inhibitor (HTS-1). The overall structure of the FRB domain is very similar to 
      that seen in the ternary complex formed with FKBP12 and the immunosuppressive 
      drug rapamycin; however, there are significant changes within the 
      rapamycin-binding site with important consequences for rational drug design. The 
      surface of the FRB domain contains a number of distinctive features that have 
      previously escaped attention, including a potential new regulatory site on the 
      opposite face to that involved in the binding of rapamycin, which displays the 
      features expected for a specific binding site for a small molecule. The 
      interaction sites for phosphatidic acid and HTS-1 were found to closely match the 
      site responsible for rapamycin binding. In addition, the structures determined 
      for the FRB-phosphatidic acid and FRB-HTS-1 complexes revealed a striking 
      similarity between the conformations of buried portions of the ligands and that 
      seen for the rapamycin backbone in contact with the domain. Our findings further 
      highlight the importance of the FRB domain in small molecule-mediated regulation 
      of mTOR, demonstrate the ability to identify novel inhibitors of mTOR that bind 
      tightly to the rapamycin-binding site in the absence of FKBP12, and identify a 
      potential new regulatory site that may be exploited in the design of new 
      anticancer drugs.
FAU - Veverka, V
AU  - Veverka V
AD  - Department of Biochemistry, University of Leicester, Leicester, UK.
FAU - Crabbe, T
AU  - Crabbe T
FAU - Bird, I
AU  - Bird I
FAU - Lennie, G
AU  - Lennie G
FAU - Muskett, F W
AU  - Muskett FW
FAU - Taylor, R J
AU  - Taylor RJ
FAU - Carr, M D
AU  - Carr MD
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070806
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Ligands)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphatidic Acids)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Binding Sites
MH  - Drug Design
MH  - Humans
MH  - Ligands
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes
MH  - Phosphatidic Acids/*pharmacology
MH  - Protein Structure, Tertiary
MH  - Proteins
MH  - Sirolimus/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tacrolimus Binding Protein 1A/*metabolism
MH  - Transcription Factors/antagonists & inhibitors/chemistry/*drug effects
EDAT- 2007/08/09 09:00
MHDA- 2008/04/23 09:00
CRDT- 2007/08/09 09:00
PHST- 2007/08/09 09:00 [pubmed]
PHST- 2008/04/23 09:00 [medline]
PHST- 2007/08/09 09:00 [entrez]
AID - 1210693 [pii]
AID - 10.1038/sj.onc.1210693 [doi]
PST - ppublish
SO  - Oncogene. 2008 Jan 24;27(5):585-95. doi: 10.1038/sj.onc.1210693. Epub 2007 Aug 6.