PMID- 26651998
OWN - NLM
STAT- MEDLINE
DCOM- 20170110
LR  - 20181113
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 4
DP  - 2015 Dec 10
TI  - Ternatin and improved synthetic variants kill cancer cells by targeting the 
      elongation factor-1A ternary complex.
LID - e10222 [pii]
LID - 10.7554/eLife.10222 [doi]
AB  - Cyclic peptide natural products have evolved to exploit diverse protein targets, 
      many of which control essential cellular processes. Inspired by a series of 
      cyclic peptides with partially elucidated structures, we designed synthetic 
      variants of ternatin, a cytotoxic and anti-adipogenic natural product whose 
      molecular mode of action was unknown. The new ternatin variants are cytotoxic 
      toward cancer cells, with up to 500-fold greater potency than ternatin itself. 
      Using a ternatin photo-affinity probe, we identify the translation elongation 
      factor-1A ternary complex (eEF1A.GTP.aminoacyl-tRNA) as a specific target and 
      demonstrate competitive binding by the unrelated natural products, didemnin and 
      cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer 
      resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface 
      as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic 
      elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are 
      common targets for the evolution of cytotoxic natural products.
FAU - Carelli, Jordan D
AU  - Carelli JD
AUID- ORCID: 0000-0001-7625-7505
AD  - Chemistry and Chemical Biology Graduate Program, University of California, San 
      Francisco, San Francisco, United States.
FAU - Sethofer, Steven G
AU  - Sethofer SG
AD  - Department of Cellular and Molecular Pharmacology, University of California, San 
      Francisco, San Francisco, United States.
FAU - Smith, Geoffrey A
AU  - Smith GA
AD  - Chemistry and Chemical Biology Graduate Program, University of California, San 
      Francisco, San Francisco, United States.
FAU - Miller, Howard R
AU  - Miller HR
AD  - Novartis Institutes for BioMedical Research, Cambridge, United States.
FAU - Simard, Jillian L
AU  - Simard JL
AD  - Department of Cellular and Molecular Pharmacology, University of California, San 
      Francisco, San Francisco, United States.
FAU - Merrick, William C
AU  - Merrick WC
AD  - Department of Biochemistry, School of Medicine, Case Western Reserve University, 
      Cleveland, United States.
FAU - Jain, Rishi K
AU  - Jain RK
AD  - Novartis Institutes for BioMedical Research, Cambridge, United States.
FAU - Ross, Nathan T
AU  - Ross NT
AD  - Novartis Institutes for BioMedical Research, Cambridge, United States.
FAU - Taunton, Jack
AU  - Taunton J
AD  - Department of Cellular and Molecular Pharmacology, University of California, San 
      Francisco, San Francisco, United States.
LA  - eng
GR  - T32 GM007618/GM/NIGMS NIH HHS/United States
GR  - T32 GM064337/GM/NIGMS NIH HHS/United States
GR  - Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151210
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Mutant Proteins)
RN  - 0 (Peptide Elongation Factor 1)
RN  - 0 (Peptides, Cyclic)
RN  - 148619-41-4 (ternatin heptapeptide)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - 9014-25-9 (RNA, Transfer)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/*pharmacology
MH  - *Cell Death
MH  - Cell Line, Tumor
MH  - Drug Resistance
MH  - Guanosine Triphosphate/metabolism
MH  - Humans
MH  - Mutant Proteins/antagonists & inhibitors/genetics
MH  - Mutation
MH  - Peptide Elongation Factor 1/*antagonists & inhibitors/genetics
MH  - Peptides, Cyclic/chemical synthesis/*pharmacology
MH  - Protein Binding
MH  - RNA, Transfer/metabolism
PMC - PMC4786417
OTO - NOTNLM
OT  - biochemistry
OT  - cancer
OT  - cell biology
OT  - cyclic peptide
OT  - elongation factor-1A
OT  - human
OT  - natural product
OT  - protein synthesis
OT  - target identification
COIS- The authors declare that no competing interests exist.
EDAT- 2015/12/15 06:00
MHDA- 2017/01/11 06:00
PMCR- 2015/12/11
CRDT- 2015/12/15 06:00
PHST- 2015/07/20 00:00 [received]
PHST- 2015/11/26 00:00 [accepted]
PHST- 2015/12/15 06:00 [entrez]
PHST- 2015/12/15 06:00 [pubmed]
PHST- 2017/01/11 06:00 [medline]
PHST- 2015/12/11 00:00 [pmc-release]
AID - e10222 [pii]
AID - 10222 [pii]
AID - 10.7554/eLife.10222 [doi]
PST - epublish
SO  - Elife. 2015 Dec 10;4:e10222. doi: 10.7554/eLife.10222.