Document Detail


Response to Klyuyev and Vassylyev: on the mechanism of tagetitoxin inhibition of transcription.
MedLine Citation:
PMID:  22414748     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In their commentary, Klyuyev and Vassylyev dispute a model of transcription inhibition by tagetitoxin (Tgt) proposed by us based on biochemical analysis and computational docking. We maintain that, although an alternative explanation can be provided for any single observation reported by us, taken together our results support a model in which Tgt acts by trapping the trigger loop (TL) in an inactive state (Artsimovitch et al.). This model is consistent with all the data collected with a physiological target for the inhibitor, the transcription elongation complex (EC). The Tgt-binding pose in our model is indeed different from that observed in the structure of the Thermus thermophilus RNA polymerase (RNAP) holoenzyme in the absence of nucleic acids (Vassylyev et al. Nat Struct Mol Biol 2005; 12:1086). The latter can hardly be considered a dogma because RNAP undergoes conformational changes in the course of the transcription cycle and during catalysis and small molecules containing phosphates likely bind to several sites on RNAP, with the crystallographic site/pose not necessarily being the one most relevant mechanistically. Furthermore, the model proposed based on the Tgt/holoenzyme structure does not explain the inhibitor's effects on transcript elongation and RNAP translocation. These arguments necessitate further inquiry into the mechanism of inhibition by Tgt by techniques orthogonal to X-ray crystallography. In our opinion, elucidation of a molecular mechanism of any RNAP inhibitor and the follow-up design of more potent derivatives requires a combination of approaches, including genetics, biochemistry, biophysics, X-ray crystallography and computational analysis.
Authors:
Vladimir Svetlov; Irina Artsimovitch; Evgeny Nudler
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Publication Detail:
Type:  Comment; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-03-01
Journal Detail:
Title:  Transcription     Volume:  3     ISSN:  2154-1272     ISO Abbreviation:  Transcription     Publication Date:    2012 Mar-Apr
Date Detail:
Created Date:  2012-04-27     Completed Date:  2012-06-28     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101530967     Medline TA:  Transcription     Country:  United States    
Other Details:
Languages:  eng     Pagination:  51-5     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, New York University School of Medicine, New York, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
DNA-Directed RNA Polymerases / metabolism*
Dicarboxylic Acids / metabolism*
Enzyme Inhibitors / metabolism*
Organophosphorus Compounds / metabolism*
Chemical
Reg. No./Substance:
0/Dicarboxylic Acids; 0/Enzyme Inhibitors; 0/Organophosphorus Compounds; 87913-21-1/tagetitoxin; EC 2.7.7.6/DNA-Directed RNA Polymerases
Comments/Corrections
Comment On:
Transcription. 2012 Mar-Apr;3(2):46-50   [PMID:  22414754 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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